Synthesis method and application of 3-trifluoromethyl quinoline compound

Abstract

The invention discloses a method for preparing a 3-trifluoromethyl quinoline compound, and belongs to the field of organic synthesis. According to the method, the organic solvent, the rhodium catalyst, the indole compound, the alkali and the alpha-trifluoromethyl diazonium sulfonium salt compound are mixed, the single carbon atom insertion ring expansion reaction is carried out, the 3-trifluoromethyl quinoline compound is obtained, the reaction raw materials, the catalyst, the alkali and the solvent used in the method are simple and easy to obtain and wide in source, operation is convenient, and the method is suitable for industrial production. The method has the advantages of high atom economy, simple process and the like, and has important application value in the field of drug synthesis.

Description

Technical Field

[0001] The invention relates to a method for preparing 3-trifluoromethylquinoline compounds, and belongs to the field of organic synthesis. Background Art

[0002] Fluorine has a small atomic radius, low orbital energy, and strong electronegativity. Therefore, when fluorine atoms or fluorine-containing groups are introduced into organic compounds, it will not cause changes in steric hindrance, but its inductive effect, pseudo-effect, blocking effect, lipophilic effect, and hydrogen bonding effect will significantly change the physical and chemical properties and biological activities of the molecules. As an important fluorine-containing group, trifluoromethyl is widely used in biomedicine, agricultural chemicals, and materials science, such as drugs Celecoxib, Efavirenz, Etofenamate, and pesticides Picoxystrobin and Fluazinam. However, natural products containing trifluoromethyl are very rare, so it is a significant task to develop corresponding synthetic methods to introduce trifluoromethyl into molecules to improve the biological activity of compounds.

[0003] In addition, quinoline compounds, as an important skeleton, are widely present in drug molecules. Quinoline active functional groups are important building blocks for new drug development, and are the structural nuclei or pharmacophores of many innovative drugs and natural products. Quinoline derivatives have a variety of significant biological activities. The currently reported synthesis methods of 3-trifluoromethylquinoline mainly include the coupling reaction of sodium trifluoromethanesulfinate or (trifluoromethyl)trimethylsilane with 3-quinolineboronic acid, but most of these methods rely on some pre-functionalized substrates and require additional chemical oxidants or high temperature conditions. At present, it is still difficult to achieve a one-pot synthesis of 3-trifluoromethylquinoline compounds using simple and readily available raw materials. Therefore, exploring a simpler method to achieve a one-step synthesis of 3-trifluoromethylquinoline compounds based on simple and readily available commercial raw materials is of great significance in the fields of organic chemistry and medicinal chemistry. Summary of the invention

[0004] The invention aims at the deficiencies of the prior art and provides a method for preparing 3-trifluoromethylquinoline compounds. The preparation method has simple and readily available raw materials, a one-step reaction, low cost, high yield, simple process and high atom economy.

[0005] The invention uses indole compounds and α-trifluoromethyl diazonium sulfonium salts which are easily available as raw materials, and prepares 3-trifluoromethyl quinoline compounds in an organic solvent under the action of a rhodium catalyst and a base. The invention is characterized in that the indole compounds, α-trifluoromethyl diazonium sulfonium salts, rhodium catalysts and bases are added into the organic solvent, and the mixture is stirred for 2 to 48 hours at a reaction temperature of -50 to 80 DEG C in an argon or nitrogen atmosphere, and the 3-trifluoromethyl quinoline compounds are separated and purified by column chromatography.

[0006] The indole compound has a structure shown in Formula I, and the α-trifluoromethyl diazonium sulfonium salt compound has a structure shown in Formula II.

[0007]

[0008] Among them, R 1 ~R 5 Selected from H, methyl, ethyl, methoxy, acetoxy, amino-tert-butyloxycarbonyl, phenyl, ester, nitro, and halogen.

[0009] In the present invention, the rhodium catalyst is any one of bis[(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid) rhodium], dimerized rhodium acetate, dimerized rhodium trifluoroacetate, tetracaprolactam dirhodium, tetrakis(triphenylacetic acid) dirhodium and dimerized rhodium octanoate.

[0010] In the present invention, the base is any one of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, sodium hexafluorophosphate, potassium hexafluorophosphate, lithium hexafluorophosphate and sodium acetate. In the present invention, the base compound is mainly used to neutralize the trifluoromethanesulfonic acid produced during the reaction to facilitate the reaction to proceed in the forward direction.

[0011] The invention also provides the application of the technology in preparing naproxen, ibuprofen, isoxacic acid, estrone, indomethacin, vitamin E, raputimonoindole and verticillatine B drug derivatives and adapalene drug molecule analogs. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 Schematic diagram of the single crystal X-ray diffraction structure of compound 1 obtained in Example 1;

[0013] Figure 2 The hydrogen nuclear magnetic resonance spectrum of compound 1 obtained in Example 1;

[0014] Figure 3 The carbon NMR spectrum of compound 1 obtained in Example 1;

[0015] Figure 4 The NMR fluorine spectrum of compound 1 obtained in Example 1. DETAILED DESCRIPTION

[0016] The present invention provides a 3-3-trifluoromethylquinoline compound having a structure shown in Formula I:

[0017]

[0018] Among them, R 1 ~R 5 Selected from H, methyl, ethyl, methoxy, acetoxy, amino-tert-butyloxycarbonyl, phenyl, ester, nitro, and halogen.

[0019] The 3-trifluoromethylquinoline compounds provided by the present invention contain quinoline active functional groups with potential biological activity, are structural mother nuclei or pharmacophores of many innovative drugs and natural products, and are conducive to promoting the development of the pharmaceutical industry.

[0020] The present invention also provides a method for preparing 3-trifluoromethylquinoline compounds, comprising the following steps: using indole compounds and α-trifluoromethyldiazonium sulfonium salt as raw materials, preparing 3-trifluoromethylquinoline compounds in an organic solvent under the action of a rhodium catalyst and a base.

[0021] The indole compound has a structure shown in Formula II, and the α-trifluoromethyl diazonium sulfonium salt compound has a structure shown in Formula III.

[0022]

[0023] Among them, R 2 ~R 5 is selected from H, methyl, methoxy, acetoxy, amino-tert-butyloxycarbonyl, phenyl, ester, nitro, halogen, R 1 The reaction formula for the above-mentioned single carbon atom insertion ring expansion reaction is shown in formula (1):

[0024]

[0025] Among them, compound 1 is an indole compound, compound 2 is an α-trifluoromethyldiazoniumsulfonium salt compound, and compound 3 is a 3-trifluoromethylquinoline compound.

[0026] In the present invention, the rhodium catalyst is any one of bis[(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid) rhodium], dimerized rhodium acetate, dimerized rhodium trifluoroacetate, tetracaprolactam dirhodium, tetrakis(triphenylacetic acid) dirhodium and dimerized rhodium octanoate.

[0027] In the present invention, the base is any one of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, sodium hexafluorophosphate, potassium hexafluorophosphate, lithium hexafluorophosphate and sodium acetate. In the present invention, the base compound is mainly used to neutralize the trifluoromethanesulfonic acid produced during the reaction to facilitate the reaction to proceed in the forward direction.

[0028] In the present invention, the molar ratio of the indole compound to the α-trifluoromethyldiazonium sulfonium salt compound is preferably 1:1-4, more preferably 1:1-3; the molar ratio of the indole compound to the base compound is preferably 1:1-4, more preferably 1:3; the molar ratio of the indole compound to the rhodium catalyst is preferably 1:0.01-0.05, more preferably 1:0.01-0.04.

[0029] In the present invention, the organic solvent is any one of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, benzene and toluene. The present invention has no special limitation on the amount of the organic solvent, as long as it can dissolve the reaction raw materials. In the embodiment of the present invention, the ratio of the indole compound to the organic solvent is preferably 1 mmol: 10 to 30 mL. More preferably, it is 1 mmol: 20 mL.

[0030] The present invention has no particular limitation on the mixing order of the indole compound, the α-trifluoromethyldiazoniumsulfonium salt compound, the base compound, the rhodium catalyst and the organic solvent, and the mixing order can be any.

[0031] In the present invention, the temperature for the single carbon atom insertion ring expansion reaction is preferably -50 to 80°C, more preferably -20 to 50°C; the time for the single carbon atom insertion ring expansion reaction is preferably 2 to 48 hours, more preferably 2 to 12 hours.

[0032] After the tandem reaction is completed, the present invention preferably cools the reaction solution obtained by the reaction to room temperature, and then performs column chromatography to remove the solvent in the solution obtained by column chromatography to obtain a 3-trifluoromethylquinoline compound.

[0033] The present invention has no special limitation on the cooling rate, and conventional cooling methods such as natural cooling may be used.

[0034] In the present invention, the column chromatography eluent is preferably a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of petroleum ether to ethyl acetate is preferably 30 to 1:1, more preferably 20 to 1:1.

[0035] The invention also provides the application of the technology in preparing naproxen, ibuprofen, isoxacic acid, estrone, indomethacin, vitamin E, raputimonoindole B and verticillatine B drug derivatives and adapalene drug molecule analogs.

[0036] The 3-trifluoromethylquinoline compounds and the preparation method thereof provided by the present invention are described in detail below in conjunction with the examples, but they should not be construed as limiting the scope of protection of the present invention.

[0037] Example 1

[0038]

[0039] 5-Methyl-6-bromoindole (0.2mmol), α-trifluoromethyldiazoniumsulfonium salt (0.6mmol), [(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)rhodium] (0.03mmol, 4.5mg), sodium carbonate (0.4mmol, 42.4mg) and 4.0mL of dichloroethane were added into a 10mL reaction bottle, and reacted at 0°C for 60min under argon or nitrogen atmosphere. After the reaction was completed, the mixture was spin-dried and the obtained mixture was subjected to column chromatography (the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1 to 5:1). The solvent was removed from the solution obtained by column chromatography to obtain a yellow solid with a yield of 40.5mg, a yield of 70%, and a melting point of 79.9 to 82.4°C.

[0040] The above yellow solid was characterized by single crystal X-ray diffraction. The results are as follows Figure 1 The yellow solid was characterized by NMR, and the results were as follows Figures 2-3 As shown, Figure 2 is the H NMR spectrum, Figure 3 is the carbon nuclear magnetic resonance spectrum, Figure 4 It is the NMR fluorine spectrum, and the specific result data are as follows:

[0041] 1 H NMR (400MHz, CDCl3) δ9.00(s,1H),8.37(s,1H),8.29(s,1H),7.70(s,1H),2.58(s,3H).

[0042] 13 C NMR(101MHz,CDCl3)δ148.4,146.2(q,J=3.0Hz),138.5,133.2(q,J=4.1Hz),1 32.7,130.1,128.6,125.4,123.9(q,J=32.9Hz),123.7(q,J=272.4Hz),23.4.

[0043] 19 F NMR(376MHz, CDCl3)δ-61.91(s,3F).

[0044] HRMS(ESI-TOF):calculated for C 11 H7BrF3N[M+H] + 289.9787; found 289.9789.

[0045] Example 2

[0046]

[0047] The 5-methyl-6-bromoindole in Example 1 was replaced by indole, and the other conditions were the same as those in Example 1. Finally, a yellow solid was obtained with a yield of 34.7 mg, a yield of 88%, and a melting point of 35.7-37.8°C.

[0048] The yellow solid was characterized by NMR. Figures 1 to 3 As shown, Figure 1 is the H NMR spectrum, Figure 2 is the carbon nuclear magnetic resonance spectrum, Figure 3 It is the NMR fluorine spectrum. The specific data are as follows:

[0049] 1 H NMR (400MHz, CDCl3) δ9.11 (s, 1H), 8.45 (s, 1H), 8.19 (d, J = 8.6Hz, 1H), 7.92 (d, J = 9.5Hz, 1H), 7.86 (t, J = 7.7Hz, 1H), 7.66 (t, J = 8.1Hz, 1H).

[0050] 13 C NMR (101MHz, CDCl3) δ149.4, 146.1 (q, J = 3.6Hz), 134.0 (q, J = 4.0Hz), 131.8, 129.6, 128.6, 128.0, 126.3, 123.8 (q, J = 272.5Hz), 123.6 (q, J = 33.1Hz).

[0051] 19 F NMR(376MHz, CDCl3)δ-61.82(s,3F).

[0052] HRMS(ESI-TOF):calculated for C 10 H6F3N[M+H] + 198.0525; found 198.0536.

[0053] Example 3

[0054]

[0055] The 5-methyl-6-bromoindole in Example 1 was replaced by 4-methylindole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained, with a yield of 26.1 mg, a yield of 62%, and a melting point of 36.1-36.7° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0056] 1 H NMR (400MHz, CDCl3) δ9.09 (s, 1H), 8.57 (s, 1H), 8.01 (d, J = 8.5Hz, 1H), 7.71 (t, J = 7.8Hz, 1H), 7.46 (d, J = 7.0Hz, 1H), 2.72 (s, 3H).

[0057] 13 C NMR (101MHz, CDCl3) δ149.8, 145.6 (q, J = 2.9Hz), 135.8, 131.6, 130.6 (q, J = 4. 1Hz), 128.6, 127.9, 125.9, 124.0 (q, J = 272.2Hz), 123.2 (q, J = 32.5Hz), 18.6.

[0058] 19 F NMR (376MHz, CDCl3) δ-61.59 (s, 3F).

[0059] HRMS(ESI-TOF):calculated for C 11 H8F3N[M+H] + 212.0682; found 212.0690.

[0060] Example 4

[0061]

[0062] The 5-methyl-6-bromoindole in Example 1 was replaced by 4-methoxyindole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained with a yield of 23.2 mg, a yield of 51%, and a melting point of 34.4-35.6° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0063] 1 H NMR (400MHz, CDCl3) δ9.10 (s, 1H), 8.91 (s, 1H), 7.82–7.74 (m, 2H), 6.97 (d, J = 7.3Hz, 1H), 4.05 (s, 3H).

[0064] 13C NMR (101MHz, CDCl3) δ155.8, 150.2, 146.5 (q, J = 3.4Hz), 132.1, 129.3 (q, J = 4. 0Hz), 124.0 (q, J = 272.3Hz), 122.8 (q, J = 32.7Hz), 121.5, 119.1, 105.6, 56.1.

[0065] 19 F NMR(376MHz, CDCl3)δ-61.61(s,3F).

[0066] HRMS(ESI-TOF):calculated for C 11 H8F3NO[M+H] + 228.0631; found 228.0640.

[0067] Example 5

[0068]

[0069] The 5-methyl-6-bromoindole in Example 1 was replaced with 4-acetoxyindole to finally obtain a yellow solid with a yield of 25.0 mg, a yield of 49%, and a melting point of 66.1-67.8° C. The yellow solid was characterized by NMR, and the specific result data are as follows:

[0070] 1 H NMR (400MHz, CDCl3) δ9.11(s,1H),8.49(s,1H),8.07(d,J=8.6Hz,1H),7.83(t,J=8.1Hz,1H),7.46(d,J=7.7Hz,1H),2.48(s,3H).

[0071] 13 C NMR (101MHz, CDCl3) δ169.0, 149.9, 146.6, 146.6 (q, J = 3.37Hz), 131.4, 128.3 (q, J=4.2Hz), 127.4, 123.9 (q, J=33.1Hz), 123.6 (q, J=272.5Hz), 120.5, 120.2, 21.1.

[0072] 19 F NMR (376MHz, CDCl3) δ-61.84 (s, 3F).

[0073] HRMS(ESI-TOF):calculated for C 12 H8F3NO2[M+H]+ 256.0580; found 256.0587.

[0074] Example 6

[0075]

[0076] The 5-methyl-6-bromoindole in Example 1 was replaced by 4-amino-tert-butyloxycarbonylindole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained with a yield of 22.5 mg, a yield of 52%, and a melting point of 117.9-118.9° C. The yellow solid was characterized by NMR, and the specific result data are as follows:

[0077] 1 H NMR (400MHz, CDCl3) δ9.03(s,1H),8.53(s,1H),7.89(d,J=8.3Hz,1H),7.83(d,J=5.0Hz,1H),7.73(t,J=8.0Hz,1H),7.36(brs,1H),1.54(s,9H).

[0078] 13 C NMR (101MHz, CDCl3) δ153.8, 149.6, 145.9 (q, J = 3.9Hz), 134.3, 131.8, 128.8, 126.2, 123.8 (q, J = 272.5Hz), 123.1 (q, J = 32.9Hz), 121.7, 120.9, 81.7, 28.4.

[0079] 19 F NMR (376MHz, CDCl3) δ-61.68 (s, 3F).

[0080] HRMS(ESI-TOF):calculated for C 15 H 15 F3N2O2[M+H] + 313.1158; found 313.1165.

[0081] Example 7

[0082]

[0083] The 5-methyl-6-bromoindole in Example 1 was replaced by 4-chloroindole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained, with a yield of 28.4 mg, a yield of 66%, and a melting point of 32.7-33.5° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0084] 1 H NMR (400MHz, CDCl3) δ9.11 (s, 1H), 8.69 (s, 1H), 7.98 (d, J = 8.6Hz, 1H), 7.77 (q, J = 7.9Hz, 1H), 7.31 (t, J = 8.6Hz, 1H).

[0085] 13 C NMR (101MHz, CDCl3) δ158.2 (d, J = 257.7Hz), 149.9, 147.1 (q, J = 3.6Hz), 131.6 (d, J = 9.0Hz), 127.8 (p, J = 4.2Hz ), 125.6 (d, J = 4.2Hz), 123.9 (q, J = 33.0Hz), 123.6 (q, J = 272.4Hz), 117.4 (d, J = 16.3Hz), 111.7 (d, J = 19.1Hz).

[0086] 19 F NMR (376MHz, CDCl3) δ-62.04 (s, 3F), -121.05 (dd, J = 9.7, 5.6Hz, 1F).

[0087] HRMS(ESI-TOF):calculated for C 10 H5F4N[M+H] + 216.0431; found 216.0438.

[0088] Example 8

[0089]

[0090] The 5-methyl-6-bromoindole in Example 1 was replaced by 4-nitroindole, and the other conditions were the same as those in Example 1, and a brown solid was finally obtained, with a yield of 35.8 mg, a yield of 74%, and a melting point of 48.8-50.1° C. The brown solid was characterized by NMR, and the specific result data are as follows:

[0091] 1 H NMR (400MHz, CDCl3) δ9.33 (s, 1H), 9.20 (s, 1H), 8.51 (d, J = 7.4Hz, 2H), 7.96 (t, J = 8.1Hz, 1H).

[0092] 13C NMR (101MHz, CDCl3) δ 149.3, 147.6 (q, J = 2.8Hz), 145.8, 136.8, 130.5 (q, J = 4.3Hz), 129.9, 126.5 (q, J = 33.3Hz), 126.2, 123.3 (q, J = 273.1Hz), 119.6.

[0093] 19 F NMR(376MHz, CDCl3)δ-62.22(s,3F).

[0094] HRMS(ESI-TOF):calculated for C 10 H5F3N2O2[M+H] + 243.0376; found 243.0385.

[0095] Example 9

[0096]

[0097] The 5-methyl-6-bromoindole in Example 1 was replaced by 5-ethylindole, and the other conditions were the same as those in Example 1, and finally a brown liquid was obtained, with a yield of 36.0 mg and a yield of 80%. The yellow liquid was characterized by NMR, and the specific result data were as follows:

[0098] 1 H NMR (400MHz, CDCl3) δ9.02 (s, 1H), 8.36 (s, 1H), 8.09 (d, J = 8.4Hz, 1H), 7.69 (d, J = 8.7Hz, 1H), 7.66 (s, 1H), 2.85 (q, J = 7.6Hz, 2H), 1.33 (t, J = 7.6Hz, 3H).

[0099] 13 C NMR (101MHz, CDCl3) δ148.3, 145.3–145.1 (m), 144.4, 133.5 (q, J = 4.0Hz), 133. 2,129.4,126.5,126.1,123.9(q,J=272.3Hz),123.6(q,J=32.7Hz),28.9,15.3.

[0100] 19 F NMR (376MHz, CDCl3) δ-61.80 (s, 3F).

[0101] HRMS(ESI-TOF):calculated for C 12 H 10F3N[M+H] + 226.0838; found 226.0848.

[0102] Example 10

[0103]

[0104] The 5-methyl-6-bromoindole in Example 1 was replaced by 5-benzyloxyindole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained with a yield of 46.1 mg, a yield of 76%, and a melting point of 77.4-78.8° C. The yellow solid was characterized by NMR, and the specific result data are as follows:

[0105] 1 H NMR (400MHz, CDCl3) δ9.04–9.00(m,1H),8.37–8.33(m,1H),8.18–8.12(m,1H),7.63(d,J= 9.2Hz,1H),7.55(d,J=7.3Hz,2H),7.49(t,J=7.3Hz,2H),7.46–7.40(m,1H),5.26(s,2H).

[0106] 13 C NMR (101MHz, CDCl3) δ157.9, 145.7, 143.64 (q, J = 3.6Hz), 136.1, 132.6 (q, J = 4.1Hz), 131.1, 128.8,128.4,127.6,127.6,125.1,123.9(q,J=32.6Hz),123.9(q,J=272.5Hz),107.0,70.5.

[0107] 19 F NMR(376MHz, CDCl3)δ-61.71.(s,3F).

[0108] HRMS(ESI-TOF):calculated for C 17 H 12 F3NO[M+H] + 304.0944; found 304.0952.

[0109] Embodiment 11

[0110]

[0111] The 5-methyl-6-bromoindole in Example 1 was replaced with 5-acetylaminoindole to finally obtain a yellow solid with a yield of 20.3 mg, a yield of 40%, and a melting point of 143.6-146.2° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0112] 1 H NMR (400MHz, CDCl3) δ8.96 (s, 1H), 8.46 (s, 2H), 8.32 (s, 1H), 8.05 (d, J = 9.0Hz, 1H), 7.71 (d, J = 9.0Hz, 1H), 2.26 (s, 3H).

[0113] 13 C NMR (101MHz, CDCl3) δ169.4, 146.3, 144.8 (d, J = 3.3Hz), 137.5, 133.9 (q, J = 3.9Hz ),130.1,127.1,125.6,124.3(q,J=33.0Hz),123.7(q,J=272.5Hz),116.6,24.8.

[0114] 19 F NMR(376MHz, CDCl3)δ-61.91(s,3F).

[0115] HRMS(ESI-TOF):calculated for C 12 H9F3N2O[M+H] + 255.0740; found 255.0750.

[0116] Example 12

[0117]

[0118] The 5-methyl-6-bromoindole in Example 1 was replaced by 4-amino-tert-butyloxycarbonylindole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained with a yield of 41.8 mg, a yield of 73%, and a melting point of 141.3-142.0° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0119] 1 H NMR (400MHz, CDC3) δ8.95(s,1H),8.30(s,1H),8.21(s,1H),8.05(d,J=9.2Hz,1H),7.62(d,J=9.0Hz,1H),7.31(brs,1H),1.53(s,9H).

[0120] 13 C NMR (101MHz, CDCl3) δ152.8,146.0,144.4,138.0,133.4(q,J=4.0Hz),130.2, 127.3, 124.9, 124.1 (q, J = 32.7Hz), 123.8 (q, J = 272.3Hz), 114.3, 81.5, 28.4.

[0121] 19 F NMR(376MHz, CDCl3)δ-61.92(s,3F).

[0122] HRMS(ESI-TOF):calculated for C 15 H 15 F3N2O2[M+H] + 313.1158; found 313.1169.

[0123] Embodiment 13

[0124]

[0125] The 5-methyl-6-bromoindole in Example 1 was replaced with 5-methylformate indole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained with a yield of 22.4 mg, a yield of 44%, and a melting point of 124.7-126.9° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0126] 1 H NMR (400MHz, CDCl3) δ9.15(s,1H),8.65(s,1H),8.52(s,1H),8.40(s,1H),8.19(s,1H),3.99(s,3H).

[0127] 13 C NMR (101MHz, CDCl3) δ149.7, 147.2, 138.1, 133.9 (q, J = 3.7Hz), 129.8, 129.3, 128.8, 124.7, 123.9 (q, J = 33.0Hz), 123.6 (q, J = 272.5Hz).

[0128] 19 F NMR (376MHz, CDCl3) δ-62.00 (s, 3F).

[0129] HRMS(ESI-TOF):calculated for C 12 H8F3NO2[M+H] +256.0580; found 256.0585.

[0130] Embodiment 14

[0131]

[0132] The 5-methyl-6-bromoindole in Example 1 was replaced by 5-chloroindole, and the other conditions were the same as those in Example 1, and a white solid was finally obtained, with a yield of 37.4 mg, a yield of 81%, and a melting point of 68.0-69.4° C. The white solid was characterized by NMR, and the specific result data are as follows:

[0133] 1 H NMR (400MHz, CDCl3) δ9.08 (s, 1H), 8.36 (s, 1H), 8.13 (d, J = 9.0Hz, 1H), 7.90 (s, 1H), 7.79 (d, J = 9.0Hz, 1H).

[0134] 13 C NMR (101MHz, CDCl3) δ147.9,146.5–146.2(m),134.2,133.3–133.0(m),132.9,131.4,127.3,127.1,124.7(q,J=33.4Hz),123.6(q,J=272.5Hz).

[0135] 19 F NMR(376MHz, CDCl3)δ-62.01(s,3F).

[0136] HRMS(ESI-TOF):calculated for C 10 H5ClF3N[M+H] + 232.0135; found 232.0145.

[0137] Embodiment 15

[0138]

[0139] The 5-methyl-6-bromoindole in Example 1 was replaced by 6-methylindole, and the other conditions were the same as those in Example 1, and a white solid was finally obtained, with a yield of 25.7 mg, a yield of 61%, and a melting point of 66.3-67.1° C. The white solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0140] 1H NMR (400MHz, CDCl3) δ9.05 (s, 1H), 8.39 (s, 1H), 7.96 (s, 1H), 7.80 (d, J = 8.3Hz, 1H), 7.49 (d, J = 8.4Hz, 1H), 2.60 (s, 3H).

[0141] 13 C NMR (101MHz, CDCl3) δ149.5,146.2–146.0(m),142.9,134.0–133.8(m),130 .5,128.6,128.3,124.5,123.9(q,J=271.7Hz),123.0(q,J=33.2Hz),22.2.

[0142] 19 F NMR (376MHz, CDCl3) δ-61.65 (s, 3F).

[0143] HRMS(ESI-TOF):calculated for C 11 H8F3N[M+H] + 212.0682; found 212.0691.

[0144] Example 16

[0145]

[0146] The 5-methyl-6-bromoindole in Example 1 was replaced by 6-benzyloxyindole, and the other conditions were the same as those in Example 1, and a white solid was finally obtained with a yield of 48.5 mg, a yield of 80%, and a melting point of 96.8-98.0° C. The white solid was characterized by NMR, and the specific result data are as follows:

[0147] 1 H NMR (400MHz, CDCl3) δ9.02 (s, 1H), 8.31 (s, 1H), 7.78 (d, J = 9.0Hz, 1H), 7.56 (s, 1H) ,7.49(d,J=7.3Hz,2H),7.42(t,J=7.3Hz,2H),7.37(d,J=7.6Hz,2H),5.22(s,2H).

[0148] 13C NMR (101MHz, CDCl3) δ161.6,151.3,146.4(q,J=3.6Hz),136.0,133.5(q,J=4.4Hz),129.7,1 28.8,128.4,127.8,124.0(q,J=272.1Hz),121.8,121.6(q,J=33.1Hz),121.6,108.6,70.5.

[0149] 19 F NMR(376MHz, CDCl3)δ-61.35(s,3F).

[0150] HRMS(ESI-TOF):calculated for C 17 H 12 F3NO[M+H] + 304.0944; found 304.0952.

[0151] Embodiment 17

[0152]

[0153] The 5-methyl-6-bromoindole in Example 1 was replaced with 6-methylformate indole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained with a yield of 30.6 mg, a yield of 60%, and a melting point of 121.6-122.5° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0154] 1 H NMR (400MHz, CDCl3) δ9.13 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 8.22 (d, J = 8.5Hz, 1H), 7.95 (d, J = 8.5Hz, 1H), 4.00 (s, 3H).

[0155] 13 C NMR (101MHz, CDCl3) δ166.3, 148.8, 147.0 (q, J = 2.8Hz), 133.8 (q, J = 4.1Hz), 133. 2,132.0,129.0,128.7,127.5,125.2(q,J=33.1Hz),123.5(q,J=282.1Hz),52.8.

[0156] 19 F NMR(376MHz, CDCl3)δ-62.14(s,3F).

[0157] HRMS(ESI-TOF):calculated for C 12 H8F3NO2[M+H] + 256.0580; found 256.0590.

[0158] Embodiment 18

[0159]

[0160] The 5-methyl-6-bromoindole in Example 1 was replaced with 6-ethylformate indole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained, with a yield of 34.4 mg, a yield of 64%, and a melting point of 87.2-88.4° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0161] 1 H NMR (400MHz, CDCl3) δ9.15(s,1H),8.87(s,1H),8.47(s,1H),8.25(d,J=8.5Hz,1H),7.97(d,J=8.5Hz,1H),4.46(q,J=7.1Hz,2H),1.45(t,J=7.1Hz,3H).

[0162] 13 C NMR (101MHz, CDCl3) δ165.8, 148.9, 147.0 (q, J = 3.6Hz), 133.9 (q, J = 4.1Hz), 133.6, 132.0,129.0,128.6,127.6,125.1(q,J=33.1Hz),123.5(q,J=272.7Hz),61.9,14.4.

[0163] 19 F NMR(376MHz, CDCl3)δ-62.10(s,3F).

[0164] HRMS(ESI-Orbitrap):calculated for[C 15 H 18 NO4] + (M+H + ): 276.1231; found: 276.1229.

[0165] HRMS(ESI-TOF):calculated for C 13 H 10 F3NO2[M+H] + 270.0736; found 270.0746.

[0166] Embodiment 19

[0167]

[0168] The 5-methyl-6-bromoindole in Example 1 was replaced by 3-iodo-8-chlorochromone, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained with a yield of 47.6 mg, a yield of 85%, and a melting point of 246.9-247.6° C. The yellow solid was characterized by NMR, and the specific result data are as follows:

[0169] 1 H NMR (400MHz, CDCl3) δ9.26 (s, 1H), 9.08 (s, 1H), 8.58 (s, 1H), 8.45 (d, J = 8.9Hz, 1H), 8.14 (d, J = 8.9Hz, 1H).

[0170] 13 C NMR (101MHz, CDCl3) δ149.7, 148.6, 148.4 (q, J = 2.9Hz), 134.0 (q, J = 4.1Hz), 130.5, 129.5, 126.4 (q, J = 33.3Hz), 125.9, 123.2 (q, J = 273.2Hz), 121.7.

[0171] 19 F NMR(376MHz, CDCl3)δ-62.31(s,3F).

[0172] HRMS(ESI-TOF):calculated for C 10 H5F3N2O2[M+H] + 243.0376; found 243.0386.

[0173] Embodiment 20

[0174]

[0175] The 5-methyl-6-bromoindole in Example 1 was replaced by 6-chloroindole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained, with a yield of 27.7 mg, a yield of 60%, and a melting point of 50.9-52.4° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0176] 1H NMR (400MHz, CDCl3) δ9.09 (s, 1H), 8.41 (s, 1H), 8.17 (s, 1H), 7.85 (d, J = 8.0Hz, 1H), 7.60 (d, J = 7.6Hz, 1H).

[0177] 13 C NMR (101MHz, CDCl3) δ149.7, 147.2, 138.1, 133.9 (q, J = 4.3Hz), 129.8, 129.3, 128.8, 124.7, 123.9 (q, J = 33.0Hz), 123.6 (q, J = 272.5Hz).

[0178] 19 F NMR (376MHz, CDCl3) δ-61.89 (s.3F).

[0179] HRMS(ESI-TOF):calculated for C 10 H5ClF3N[M+H] + 232.0135; found 232.0145.

[0180] Embodiment 21

[0181]

[0182] The 5-methyl-6-bromoindole in Example 1 was replaced by 6-iodoindole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained with a yield of 38.8 mg, a yield of 60%, and a melting point of 79.7-80.5° C. The yellow solid was characterized by NMR, and the specific result data are as follows:

[0183] 1 H NMR (400MHz, CDCl3) δ9.05 (s, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 7.89 (d, J = 8.5Hz, 1H), 7.59 (s, 1H).

[0184] 13 C NMR (101MHz, CDCl3) δ 149.8, 146.9 (q, J = 3.6Hz), 138.8, 137.0, 134.0 (q, J = 3.9Hz), 129.5, 125.3, 124.1 (q, J = 33.1Hz), 123.6 (q, J = 272.5Hz), 98.7.

[0185] 19 F NMR (376MHz, CDCl3) δ-61.95 (s, 3F).

[0186] HRMS(ESI-TOF):calculated for C 11 H5F3IN[M+H] + 323.9492; found 323.9499.

[0187] Embodiment 22

[0188]

[0189] The 5-methyl-6-bromoindole in Example 1 was replaced by 7-methylindole, and the other conditions were the same as those in Example 1, and a yellow liquid was finally obtained with a yield of 30.8 mg and a yield of 73%. The yellow solid was characterized by NMR, and the specific result data were as follows:

[0190] 1 H NMR (400MHz, CDCl3) δ9.11 (s, 1H), 8.39 (s, 1H), 7.75 (d, J = 8.1Hz, 1H), 7.69 (d, J = 7.1Hz, 1H), 7.54 (t, J = 7.6Hz, 1H), 2.83 (s, 3H).

[0191] 13 C NMR(101MHz,CDCl3)δ148.5,145.0(q,J=3.0Hz),137.8,134.3(q,J=4.1Hz),1 32.0,127.9,126.7,126.4,124.0(q,J=272.2Hz),123.4(q,J=32.8Hz),18.2.

[0192] 19 F NMR(376MHz, CDCl3)δ-61.76(s,3F).

[0193] HRMS(ESI-TOF):calculated for C 11 H8F3N[M+H] + 212.0682; found 212.0686.

[0194] Embodiment 23

[0195]

[0196] The 5-methyl-6-bromoindole in Example 1 was replaced by 7-methoxyindole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained with a yield of 37.2 mg, a yield of 82%, and a melting point of 90.7-93.1° C. The yellow solid was characterized by NMR, and the specific result data are as follows:

[0197] 1 H NMR (400MHz, CDCl3) δ9.04 (s, 1H), 8.34 (s, 1H), 7.52 (t, J = 8.0Hz, 1H), 7.41 (d, J = 8.2Hz, 1H), 7.12 (d, J = 7.6Hz, 1H), 4.06 (s, 3H).

[0198] 13 C NMR(101MHz,CDCl3)δ155.4,144.7(q,J=3.6Hz),141.1,133.8(q,J=4.0Hz),1 28.4, 127.5, 124.2 (q, J = 32.7Hz), 123.7 (q, J = 272.5Hz), 120.1, 109.8, 56.2.

[0199] 19 F NMR(376MHz, CDCl3)δ-61.92(s,3F).

[0200] HRMS(ESI-TOF):calculated for C 11 H8F3NO[M+H] + 228.0631; found 228.0639.

[0201] Embodiment 24

[0202]

[0203] The 5-methyl-6-bromoindole in Example 1 was replaced by 7-benzyloxyindole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained, with a yield of 37.6 mg, a yield of 62%, and a melting point of 83.1-85.5° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0204] 1H NMR (400MHz, CDCl3) δ9.14 (s, 1H), 8.37 (s, 1H), 7.50 (d, J = 7.3Hz, 2H), 7.45 (d, J = 8.0Hz ,2H),7.36(t,J=7.4Hz,2H),7.30(d,J=7.2Hz,1H),7.14(d,J=7.1Hz,1H),5.44(s,2H).

[0205] 13 C NMR (101MHz, CDCl3) δ154.4,144.9(q,J=3.6Hz),141.5,136.5,133.9(q,J=4.0Hz),128.8,1 28.3,128.1,127.6,127.2,124.1(q,J=33.1Hz),123.7(q,J=272.5Hz),120.4,112.1,71.0.

[0206] 19 F NMR (376MHz, CDCl3) δ-61.85 (s, 3F).

[0207] HRMS(ESI-TOF):calculated for C 17 H 12 F3NO[M+H] + 304.0944; found 304.0954.

[0208] Embodiment 25

[0209]

[0210] The 5-methyl-6-bromoindole in Example 1 was replaced by 7-fluoroindole, and the other conditions were the same as those in Example 1, and a white solid was finally obtained, with a yield of 24.9 mg, a yield of 58%, and a melting point of 91.5-93.3° C. The white solid was characterized by NMR, and the specific result data are as follows:

[0211] 1 H NMR (400MHz, CDCl3) δ9.11 (s, 1H), 8.46 (s, 1H), 7.71 (d, J = 8.2Hz, 1H), 7.60 (q, 1H), 7.53 (t, J = 8.9Hz, 1H).

[0212] 13C NMR (101MHz, CDCl3) δ157.9 (d, J = 258.7Hz), 146.3, 139.5 (d, J = 12.4Hz), 133.9 (p, J = 4.0Hz), 128.2 (d, J=8.0Hz), 127.9, 124.7 (q, J=33.1Hz), 124.4 (d, J=4.4Hz), 123.5 (q, J=272.5Hz), 116.0 (d, J=18.9Hz).

[0213] 19 F NMR(376MHz, CDCl3)δ-62.01(s,3F),-124.08(s,1F).

[0214] HRMS(ESI-TOF):calculated for C 10 H5F4N[M+H] + 216.0431; found 216.0438.

[0215] Embodiment 26

[0216]

[0217] The 5-methyl-6-bromoindole in Example 1 was replaced by 7-chloroindole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained, with a yield of 24.0 mg, a yield of 52%, and a melting point of 58.1-59.9° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0218] 1 H NMR (400MHz, CDCl3) δ9.18 (s, 1H), 8.46 (s, 1H), 7.94 (d, J = 7.5Hz, 1H), 7.84 (d, J = 8.2Hz, 1H), 7.57 (t, J = 8.0Hz, 1H).

[0219] 13 C NMR (101MHz, CDCl3) δ 146.7 (q, J = 3.6Hz), 145.6, 134.6 (q, J = 4.4Hz), 134.0, 132.0, 128.2, 127.8, 127.7, 124.6 (q, J = 33.1Hz), 123.4 (q, J = 272.8Hz).

[0220] 19 F NMR(376MHz, CDCl3)δ-61.92(s,3F).

[0221] HRMS(ESI-TOF):calculated for C 10 H5ClF3N[M+H] + 232.0135; found 232.0145.

[0222] Embodiment 27

[0223]

[0224] The 5-methyl-6-bromoindole in Example 1 was replaced by bromoindole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained, with a yield of 24.2 mg, a yield of 44%, and a melting point of 43.3-45.1° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0225] 1 H NMR (400MHz, CDCl3) δ9.20 (s, 1H), 8.45 (s, 1H), 8.17 (d, J = 8.9Hz, 1H), 7.89 (d, J = 6.8Hz, 1H), 7.51 (t, J = 7.8Hz, 1H).

[0226] 13 C NMR (101MHz, CDCl3) δ 146.9 (q, J = 3.6Hz), 146.4, 135.6, 134.8 (q, J = 4.4Hz), 128.64, 128.61, 127.7, 125.1, 124.6 (q, J = 33.3Hz), 123.4 (q, J = 273.5Hz).

[0227] 19 F NMR (376MHz, CDCl3) δ-61.87 (s, 3F).

[0228] HRMS(ESI-TOF):calculated for C 10 H5BrF3N[M+H] + 275.9630; found 275.9639.

[0229] Embodiment 28

[0230]

[0231] The 5-methyl-6-bromoindole in Example 1 was replaced by 4,6-dimethoxyindole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained with a yield of 25.7 mg, a yield of 50%, and a melting point of 142.4-144.9° C. The yellow solid was characterized by NMR, and the specific result data are as follows:

[0232] 1 H NMR (400MHz, CDCl3) δ8.96 (s, 1H), 8.67 (s, 1H), 7.03 (s, 1H), 6.54 (s, 1H), 3.95 (d, J = 9.0Hz, 6H).

[0233] 13 C NMR (101MHz, CDCl3) δ163.4, 156.5, 151.8, 146.9 (q, J = 3.4Hz), 129.0 (q, J = 4.1 Hz), 124.3 (q, J = 273.7Hz), 120.7 (q, J = 32.9Hz), 115.1, 99.8, 99.4, 56.0, 55.9.

[0234] 19 F NMR(376MHz, CDCl3)δ-61.29(s,3F).

[0235] HRMS(ESI-TOF):calculated for C 12 H 10 F3NO2[M+H] + 258.0736; found 258.0746.

[0236] Embodiment 29

[0237]

[0238] The 5-methyl-6-bromoindole in Example 1 was replaced with 4-bromo-6-methylformate indole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained with a yield of 34.9 mg, a yield of 54%, and a melting point of 118.0-120.1° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0239] 1 H NMR (400MHz, CDCl3) δ9.16 (s, 1H), 8.81 (d, J = 4.6Hz, 2H), 8.50 (s, 1H), 4.03 (s, 3H).

[0240] 13 C NMR (101MHz, CDCl3) δ165.1, 149.5, 147.7 (q, J = 3.6Hz), 133.7 (q, J = 4.1Hz), 133. 5,131.8,131.2,128.5,126.3(q,J=33.2Hz),123.3(q,J=272.9Hz),123.1,53.1.

[0241] 19 F NMR (376MHz, CDCl3) δ-62.04 (s, 3F).

[0242] HRMS(ESI-TOF):calculated for C 12 H7BrF3NO2[M+H] + 333.9685; found 333.9695.

[0243] Embodiment 30

[0244]

[0245] The 5-methyl-6-bromoindole in Example 1 was replaced by 4-bromo-6-chloroindole, and the other conditions were the same as those in Example 1, and a white solid was finally obtained, with a yield of 32.1 mg, a yield of 52%, and a melting point of 94.3-94.9° C. The white solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0246] 1 H NMR (400MHz, CDCl3) δ9.09(s,1H),8.74(s,1H),8.13(s,1H),7.90(s,1H).

[0247] 13 C NMR (101MHz, CDCl3) δ150.1,148.0(q,J=3.6Hz),137.8,133.7(q,J=4.4Hz),132.5,128.8,125.1(q,J=33.7Hz),124.8,123.4,123.4(q,J=273.7Hz).

[0248] 19 F NMR(376MHz, CDCl3)δ-61.93(s,3F).

[0249] HRMS(ESI-TOF):calculated for C 10 H4BrClF3N[M+H] + 309.9241; found 309.9251.

[0250] Embodiment 31

[0251]

[0252] The 5-methyl-6-bromoindole in Example 1 was replaced by 4-bromo-5,7-dimethylindole, and the other conditions were the same as those in Example 1, and a white solid was finally obtained with a yield of 32.7 mg, a yield of 54%, and a melting point of 106.0-108.1° C. The white solid was characterized by NMR, and the specific result data are as follows:

[0253] 1 H NMR (400MHz, CDCl3) δ9.02(s,1H),8.80(s,1H),7.53(s,1H),2.72(s,3H),2.58(s,3H).

[0254] 13 C NMR(101MHz, CDCl3)δ147.9,144.5(q,J=3.6Hz),138.3,136.8,134.6,133.7(q, J=4.4Hz), 126.3, 124.4 (q, J=32.8Hz), 123.8 (q, J=272.9Hz), 120.9, 23.9, 17.9.

[0255] 19 F NMR (376MHz,CDCl3)δ-61.66.

[0256] HRMS(ESI-TOF):calculated for C 12 H9BrF3N[M+H] + 303.9943; found 303.9954.

[0257] Embodiment 32

[0258]

[0259] The 5-methyl-6-bromoindole in Example 1 was replaced by 5-bromo-7-methylindole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained with a yield of 37.6 mg, a yield of 65%, and a melting point of 60.5-62.9° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0260] 1 H NMR (400MHz, CDCl3) δ9.07(s,1H),8.26(s,1H),7.85(s,1H),7.73(s,1H),2.77(s,3H).

[0261] 13C NMR (101MHz, CDCl3) δ147.2, 145.2 (q, J = 2.9Hz), 140.1, 135.1, 133.1 (q, J = 4. 0Hz), 128.4, 127.4, 124.3 (q, J = 32.9Hz), 123.6 (q, J = 272.5Hz), 121.9, 17.9.

[0262] 19 F NMR(376MHz, CDCl3)δ-61.98(s,3F).

[0263] HRMS(ESI-TOF):calculated for C 11 H7BrF3N[M+H] + 289.9787; found 289.9795.

[0264] Embodiment 33

[0265]

[0266] The 5-methyl-6-bromoindole in Example 1 was replaced by 5-chloro-6-fluoroindole, and the other conditions were the same as those in Example 1, and a white solid was finally obtained with a yield of 24.9 mg, a yield of 50%, and a melting point of 92.5-94.2° C. The white solid was characterized by NMR, and the specific result data are as follows:

[0267] 1 H NMR (400MHz, CDCl3) δ9.10 (s, 1H), 8.38 (s, 1H), 8.02 (d, J = 7.6Hz, 1H), 7.92 (d, J = 9.6Hz, 1H).

[0268] 13 C NMR (101MHz, CDCl3) δ159.7 (d, J = 257.1Hz), 149.0 (d, J = 11.7Hz), 147.3 (q, J = 3.7Hz), 133 .0(q,J=5.7Hz),129.8,124.5,124.3,123.8,123.5(q,J=272.6Hz),115.0(d,J=20.9Hz).

[0269] 19 F NMR (376MHz, CDCl3) δ-61.97 (s, 3F), -107.42 (t, J = 8.5Hz, 1F).

[0270] HRMS(ESI-TOF):calculated for C 10H4ClF4N[M+H] + 250.0041; found 250.0051.

[0271] Embodiment 34

[0272]

[0273] The 5-methyl-6-bromoindole in Example 1 was replaced by 6-methylformate 7-methylindole, and the other conditions were the same as in Example 1, and a yellow solid was finally obtained, with a yield of 32.3 mg, a yield of 60%, and a melting point of 72.6-74.8° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0274] 1 H NMR (400MHz, CDCl3) δ9.13(s,1H),8.38(s,1H),7.96(d,J=8.6Hz,1H),7.73(d,J=8.6Hz,1H),3.98(s,3H),3.05(s,3H).

[0275] 13 C NMR (101MHz, CDCl3) δ168.2, 148.6, 145.5 (q, J = 2.9Hz), 140.5, 134.1 (q, J = 4.1Hz), 132.7,128.1,127.7,126.1,124.6(q,J=33.0Hz),123.7(q,J=272.5Hz),52.6,14.9.

[0276] 19 F NMR (376MHz, CDCl3) δ-62.08 (s, 3F).

[0277] HRMS(ESI-TOF):calculated for C 13 H 10 F3NO2[M+H] + 270.0736; found 270.0746.

[0278] Embodiment 35

[0279]

[0280] The 5-methyl-6-bromoindole in Example 1 was replaced by 4-methylindole, and the other conditions were the same as those in Example 1, and a yellow solid was finally obtained, with a yield of 23.6 mg, a yield of 56%, and a melting point of 62.0-63.6° C. The yellow solid was characterized by nuclear magnetic resonance, and the specific result data are as follows:

[0281] 1 H NMR (400MHz, CDCl3) δ9.06 (s, 1H), 8.17 (d, J = 10.0Hz, 2H), 7.84 (t, J = 7.6Hz, 1H), 7.68 (t, J = 8.3Hz, 1H), 2.87 (s, 3H).

[0282] 13 C NMR(101MHz, CDCl3)δ149.0,145.9(q,J=5.9Hz),145.4–145.3(m),131.3,13 0.4,127.7,127.4,124.4(q,J=274.4Hz),124.4,122.0(q,J=29.6Hz),14.8.

[0283] 19 F NMR (376MHz, CDCl3) δ-58.71 (s, 3F).

[0284] HRMS(ESI-TOF):calculated for C 11 H8F3N[M+H] + 212.0682; found 212.0690.

[0285] Embodiment 36

[0286]

[0287] The 5-methyl-6-bromoindole in Example 1 was replaced by 4-ethylindole, and the other conditions were the same as those in Example 1, and a purple solid was finally obtained with a yield of 24.7 mg, a yield of 55%, and a melting point of 54.1-55.1° C. The purple solid was characterized by NMR, and the specific result data are as follows:

[0288] 1 H NMR (400MHz, CDCl3) δ9.06 (s, 1H), 8.16 (d, J = 8.7Hz, 2H), 7.81 (t, J = 7.6Hz, 1H), 7.66 (t, J = 7.7Hz, 1H), 3.30 (q, J = 7.5Hz, 2H), 1.38 (t, J = 7.6Hz, 3H).

[0289] 13C NMR (101MHz, CDCl3) δ151.2, 149.5, 146.2 (q, J = 6.2Hz), 131.3, 130.6, 127.8, 126.4, 124.5 (q, J = 274.7Hz), 124.5, 121.2 (q, J = 29.4Hz), 22.2, 15.6.

[0290] 19 F NMR (376MHz, CDCl3) δ-58.41 (s, 3F).

[0291] HRMS(ESI-TOF):calculated for C 12 H 10 F3N[M+H] + 226.0838; found 226.0847.

[0292] Embodiment 37

[0293]

[0294] The 5-methyl-6-bromoindole in Example 1 was replaced with 1H, 1'H-5,6'-biindole, and the other conditions were the same as in Example 1, and a yellow solid was finally obtained, with a yield of 31.4 mg, a yield of 40%, and a melting point of 141.6-142.1°C. The yellow solid was characterized by NMR, and the specific result data are as follows:

[0295] 1 H NMR (400MHz, CDCl3) δ9.16(d,J=9.0Hz,2H),8.59–8.51(m,3H),8.36(d,J=8.7Hz,1H),8.32–8.24(m,2H),8.08(q,J=8.6Hz,2H).

[0296] 13 C NMR (101MHz, CDCl3) δ149.7,149.2,147.0(d,J=3.1Hz),146.7(d,J=2.9Hz),143,0,139.3,134.5(q,J=4.0Hz),134.0(q,J=3.7 Hz), 131.5, 130.7, 129.7, 128.1, 127.6, 127.3, 126.7, 125.9, 124.5 (q, J = 32.7Hz), 124.1 (q, J = 33.1Hz), 123.7 (q, J = 273.0Hz).

[0297] 19F NMR(376MHz, CDCl3)δ-61.83(s,3F),-61.90(s,3F).

[0298] HRMS(ESI-TOF):calculated for C 20 H 10 F6N2[M+H] + 393.0821; found 393.0831.

[0299] Embodiment 38

[0300]

[0301] The 5-methyl-6-bromoindole in Example 1 was replaced with an indole derivative of naproxen, and the other conditions were the same as in Example 1, and a yellow oil was finally obtained with a yield of 61.2 mg and a yield of 72%. The yellow solid was characterized by NMR, and the specific result data are as follows:

[0302] 1 H NMR(400MHz, CDCl3)δ9.06(s,1H),8.33(s,1H),8.14(d,J=9.0Hz,1H),7.81–7.75(m,3H),7.54(d,J=12.9Hz,2H),7 .48(d,J=9.2Hz,1H),7.18(d,J=8.8Hz,1H),7.16(s,1H),4.18(q,J=7.2Hz,1H),3.92(s,3H),1.75(d,J=7.0Hz,3H).

[0303] 13 C NMR (101MHz, CDCl3) δ173.0,158.0,149.8,147.3,145.8,134.8,134.0,133.7(q,J=3.8Hz),131.1,129.4,129.1,12 7.7,127.1,126.7,126.3,126.1,124.1(q,J=33.1Hz),123.6(q,J=263.6Hz),119.4,119.1,105.7,55.4,45.7,18.5.

[0304] 19 F NMR (376MHz, CDCl3) δ-61.85 (s, 3F).

[0305] HRMS(ESI-TOF):calculated for C 24 H 18 F3NO3[M+H]+ 426.1312; found 426.1322.

[0306] Embodiment 39

[0307]

[0308] The 5-methyl-6-bromoindole in Example 1 was replaced with an indole derivative of isoxacic acid, and the other conditions were the same as in Example 1, and a white solid was finally obtained with a yield of 84.3 mg, a yield of 91%, and a melting point of 132.9-134.6° C. The white solid was characterized by NMR, and the specific result data are as follows:

[0309] 1 H NMR (400MHz, CDCl3) δ9.07(s,1H),8.39(s,1H),8.27(s,1H),8.18(d,J=9.0Hz,1H),7.90(d,J=7.4Hz,1H),7.69(s,1H),7. 57(dt,J=11.8,6.2Hz,3H),7.48(t,J=7.3Hz,1H),7.37(d,J=7.1Hz,1H),7.09(d,J=8.4Hz,1H),5.21(s,2H),3.97(s,2H).

[0310] 13 C NMR (101MHz, CDCl3) δ190.9,169.7,160.9,149.6,147.4,146.3–145.6(m),140.5,136.4,135.6,133.9(q,J=4.1Hz),133.0,132. 8,131.3,129.6,129.5,128.0,127.2,126.8,126.7,125.4,124.2(q,J=33.2Hz),123.6(q,J=272.6Hz),121.6,119.3,73.8,40.4.

[0311] 19 F NMR (376MHz, CDCl3) δ-61.86 (s, 3F).

[0312] HRMS(ESI-TOF):calculated for C 26 H 16 F3NO4[M+H] + 464.1104; found 464.1114.

[0313] Embodiment 40

[0314]

[0315] The 5-methyl-6-bromoindole in Example 1 was replaced with an indole derivative of indomethacin, and the other conditions were the same as those in Example 1, and a white solid was finally obtained with a yield of 58.5 mg, a yield of 53%, and a melting point of 140.0-140.6° C. The white solid was characterized by NMR, and the specific result data are as follows:

[0316] 1 H NMR (400MHz, CDCl3) δ9.07(s,1H),8.38(s,1H),8.18(d,J=9.2Hz,1H),7.69(s,1H),7.68(s,2H),7.56(d,J=6.8Hz,1H), 7.47(d,J=6.5Hz,2H),7.08(s,1H),6.89(d,J=9.0Hz,1H),6.71(d,J=9.0Hz,1H),3.99(s,2H),3.85(s,3H),2.50(s,3H).

[0317] 13 C NMR (101MHz, CDCl3) δ169.1,168.4,156.3,149.6,147.3,146.0,139.6,136.6,133.9–133.7(m,1C),133.8,131.3,131.3,131.0 ,130.5,129.3,127.1,126.7,124.3(q,J=33.0Hz),123.6(q,J=272.6Hz),119.2,115.2,111.8,111.6,101.3,55.8,30.7,13.6.

[0318] 19 F NMR (376MHz, CDCl3) δ-61.87 (s, 3F).

[0319] HRMS(ESI-TOF):calculated for C 29 H 20 ClF3N2O4[M+Na] + 575.0956; found 575.0962.

[0320] Embodiment 41

[0321]

[0322] The 5-methyl-6-bromoindole in Example 1 was replaced with an indole derivative of vitamin E, and the other conditions were the same as in Example 1, and a brown oil was finally obtained with a yield of 79.2 mg and a yield of 65%. The brown oil was characterized by NMR, and the specific result data are as follows:

[0323] 1 H NMR (400MHz, CDCl3) δ9.14(s,1H),8.46(s,1H),8.28(s,1H),7.74–7.65(m,2H),2.68(t,J=6.8Hz,2H),2.20( s,3H),1.91(d,J=15.8Hz,8H),1.70–1.61(m,3H),1.36–1.26(m,12H),1.20–1.07(m,7H),0.91–0.88(m,14H).

[0324] 13 C NMR(101MHz, CDCl3)δ151.4,148.2,145.8,143.1,135.3,134.3–134.0(m,1C),133.0,131.8,131.7,12 9.4,129.2,126.5,123.9(q,J=272.1Hz,1C),123.9(q,J=33.0Hz,1C),122.4,117.1,75.5,40.5–40.3( m,1C),39.5,37.8–37.4(m,1C),37.5(d,J=2.4Hz,1C),33.0–32.9(m,1C),32.9–32.8(m,1C),31.3,31. 3,28.1,25.0,24.6,24.2,24.1,22.9,22.8,21.2,20.9,19.8(t,J=5.9Hz,1C),19.8,18.0,17.0,12.0.

[0325] 19 F NMR(376MHz, CDCl3)δ-61.72(s,3F).

[0326] HRMS(ESI-TOF):calculated for C 39 H 54 F3NO[M+H] + 610.4230; found 610.4240.

[0327] Embodiment 42

[0328]

[0329] The 5-methyl-6-bromoindole in Example 1 was replaced with an indole derivative of ibuprofen, and the other conditions were the same as in Example 1, and a yellow solid was finally obtained with a yield of 43.3 mg, a yield of 54%, and a melting point of 53.7-54.6° C. The yellow solid was characterized by NMR, and the specific result data are as follows:

[0330] 1 H NMR (CDCl3, 400MHz):

[0331] δ110.58(brs,1H),10.17(s,1H),8.16(d,J=6.7Hz,1H),7.58(t,J=6.6Hz,1H),7.35(t,J=5.9Hz,1H ),7.22(d,J=7.6Hz,1H),6.74-6.66(m,3H),5.87(s,2H),3.79-3.74(m,2H),2.90(t,J=7.2Hz,2H).

[0332] 13 C NMR (101MHz, CDCl3) δ173.1, 149.9, 147.3, 145.9 (d, J = 3.0Hz), 141.3, 136.9, 133.8 (q, J = 4.0Hz), 131.2, 12 9.8,127.3,127.2,126.7,124.2(q,J=33.1Hz),123.6(q,J=272.5Hz),119.2,45.4,45.2,30.3,22.5,18.6.

[0333] 19 F NMR (376MHz, CDCl3) δ-61.89 (s, 3F).

[0334] HRMS(ESI-TOF):calculated for C 23 H 22 F3NO2[M+H] + 402.1675; found 402.1684.

[0335] Embodiment 43

[0336]

[0337] The 5-methyl-6-bromoindole in Example 1 was replaced with an indole derivative of estrone, and the other conditions were the same as in Example 1, and a yellow solid was finally obtained with a yield of 54.0 mg and a yield of 62%. The yellow solid was characterized by NMR, and the specific result data are as follows:

[0338] 1 H NMR(400MHz, CDCl3)δ9.07(s,1H),8.49(s,1H),8.25–8.23(m,1H),8.15–8.06(m,2H ),7.53–7.51(m,1H),7.47–7.44(m,2H),3.04(d,J=4.8Hz,2H),2.56–2.48(m,2H),2 .37(t,J=11.2Hz,1H),2.19(t,J=8.9Hz,1H),2.10(d,J=11.8Hz,2H),2.01(d,J=12. 4Hz,1H),1.66(t,J=12.5Hz,2H),1.57(t,J=11.8Hz,3H),1.25(s,1H),0.94(s,3H).

[0339] 13 C NMR (101MHz, CDCl3) δ148.6,145.8(q,J=3.4Hz),140.8,140.2,137.5,137.1,134.3(q,J=4.1Hz),131.7,129.9,128.1,126.7,12 6.4,125.8,124.9,124.0(q,J=32.6Hz),123.8(q,J=272.3Hz),50.6,48.1,44.5,38.2,36.0,31.7,29.8,29.7,26.6,25.9,14.0.

[0340] 19 F NMR(376MHz, CDCl3)δ-61.77(s,3F).

[0341] HRMS(ESI-TOF):calculated for C 28 H 26 F3NO[M+H] + 450.2039; found 450.2047.

[0342] Embodiment 44

[0343]

[0344] The 5-methyl-6-bromoindole in Example 1 was replaced with the natural drug molecule Raputimonoindole B, and the other conditions were the same as in Example 1, and a yellow solid was finally obtained with a yield of 35.3 mg, a yield of 55%, and a melting point of 156.1-158.5° C. The yellow solid was characterized by NMR, and the specific result data are as follows:

[0345] 1 H NMR (400MHz, CDCl3) δ9.03(s,1H),8.41(s,1H),8.17–8.14(m,2H),8.11–8.02(m,2H),7.14(s,1H),3.88(s,3H).

[0346] 13 C NMR (101MHz, CDCl3) δ163.3,153.7,149.0,147.9,146.3(q,J=3.37Hz),134.1(q,J=4.0Hz),130 .4,129.2,128.0,126.6,124.5(q,J=33.2Hz),123.6(q,J=272.5Hz),122.9,121.5,106.8,52.0.

[0347] 19 F NMR(376MHz, CDCl3)δ-61.96(s,3F).

[0348] HRMS(ESI-TOF):calculated for C 16 H 10 F3NO3[M+H] + 322.0686; found 322.0695.

[0349] Embodiment 45

[0350]

[0351] The 5-methyl-6-bromoindole in Example 1 was replaced with the natural drug molecule Verticillatine B, and the other conditions were the same as in Example 1, and a yellow solid was finally obtained, with a yield of 22.5 mg, a yield of 40%, and a melting point of 117.3-118.8° C. The yellow solid was characterized by NMR, and the specific result data are as follows:

[0352] 1 H NMR (400MHz, CDCl3) δ9.19(s,1H),8.59(s,1H),8.54(s,1H),8.40(d,J=8.8Hz,1H),8.25(d ,J=9.4Hz,1H),2.99(d,J=6.8Hz,2H),2.37(dt,J=12.5,6.4Hz,1H),1.04(d,J=6.7Hz,6H).

[0353] 13C NMR (101MHz, CDCl3) δ199.2, 151.2, 148.3 (q, J = 3.0Hz), 136.5, 135.5 (q, J = 4.1Hz), 130 .4,130.2,130.0,125.8,124.6(q,J=33.2Hz),123.5(q,J=273.4Hz),47.9,25.3,22.9.

[0354] 19 F NMR (376MHz, CDCl3) δ-61.95 (s, 3F).

[0355] HRMS(ESI-TOF):calculated for C 15 H 14 F3NO[M+H] + 282.1100; found 282.1110.

[0356] Embodiment 46

[0357]

[0358] (1) 1-(5-bromo-2-methoxyphenyl)adamantane (642.5 mg, 2 mmol), 6-indoleboric acid (321.94 mg, 2 mmol), tetrakis(triphenylphosphine)palladium (115 mg, 0.1 mmol), potassium phosphate (1.69 g, 8 mmol) and ethylene glycol dimethyl ether / water (4:1, 10 mL) were added to a 20 mL Schlenk tube in sequence, the reaction system was replaced with an argon system, and the resulting reaction mixture was stirred at 60°C for 8 h. After the reaction was cooled to room temperature, the reaction system was extracted with saturated brine and dichloromethane, the combined organic phase was dried over anhydrous sodium sulfate, and after evaporating the solvent, the resulting mixture was subjected to column chromatography (the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1 to 5:1), and the solvent was removed from the solution obtained by column chromatography to obtain intermediate 46-1 as a yellow solid with a yield of 507.2 mg and a yield of 71%.

[0359] (2) The intermediate 46-1 (0.2 mmol), α-trifluoromethyl diazonium sulfonium salt (0.6 mmol), [(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid) rhodium] (0.03 mmol, 4.5 mg), sodium carbonate (0.4 mmol, 42.4 mg), and 4.0 mL of dichloroethane were added to a 10 mL reaction bottle and reacted at 0°C for 60 min under an argon or nitrogen atmosphere. After the reaction was completed, the solvent was evaporated and the resulting mixture was subjected to column chromatography (the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1 to 5:1). The solvent was removed from the solution obtained by column chromatography to obtain the target product 46-2, a white solid with a yield of 56.8 mg and a yield of 65%. The melting point was 193.1 to 193.5°C. The white solid was characterized by NMR, and the specific result data are as follows:

[0360] 1 H NMR (400MHz, CDCl3) δ9.08(s,1H),8.51(s,1H),8.25(d,J=9.2Hz,1H),8.11(d,J=8.8Hz,1H),8.05(s,1H),7. 61(s,1H),7.54(d,J=6.0Hz,1H),7.01(d,J=8.4Hz,1H),3.91(s,3H),2.20(s,6H),2.12(s,3H),1.82(s,6H).

[0361] 13 C NMR (101MHz, CDCl3) δ159.3, 148.4, 145.6, 141.4, 139.4, 134.2 (q, J = 3.7Hz), 131.8, 131.6, 129.8, 126. 8,126.1,125.9,125.2,124.0(q,J=32.7Hz),123.9(q,J=273.4Hz),112.3,55.3,40.7,37.4,37.2,29.2.

[0362] 19 F NMR(376MHz, CDCl3)δ-61.77(s,3F).

[0363] HRMS(ESI-TOF):calcd.For C 27 H 26 F3NO[M+H] + 438.2039; found 438.2049.

Claims

1. A method for preparing 3-trifluoromethylquinoline compounds, characterized in that An organic solvent, a rhodium catalyst, an indole compound of formula (I), a base and an α-trifluoromethyldiazonium salt compound of formula (II) are mixed to undergo a single carbon atom insertion ring expansion reaction to obtain a 3-trifluoromethylquinoline compound of formula (III). Formula I, Formula II, Formula III Among them, R 1 ~R 5 Selected from H, methyl, ethyl, methoxy, acetoxy, tert-butyloxycarbonyl, phenyl, ester group, nitro, halogen.

2. The method for preparing 3-trifluoromethylquinoline compounds according to claim 1, characterized in that: The rhodium catalyst is any one of bis[(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid) rhodium], dimerized rhodium acetate, dimerized rhodium trifluoroacetate, tetracaprolactam dirhodium, tetrakis(triphenylacetic acid) dirhodium and dimerized rhodium octanoate.

3. The method for preparing 3-trifluoromethylquinoline compounds according to claim 1, characterized in that: The base is any one of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, sodium hexafluorophosphate, potassium hexafluorophosphate, lithium hexafluorophosphate and sodium acetate.

4. The method for preparing 3-trifluoromethylquinoline compounds according to claim 1, characterized in that: The organic solvent is any one of 1,2-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, benzene and toluene.

5. The method for preparing 3-trifluoromethylquinoline compounds according to claim 1, characterized in that: The molar ratio of the indole compound, the α-trifluoromethyl diazonium sulfonium salt compound, the base and the rhodium catalyst is 1:(1-4):(1-4):(0.01-0.05).

6. The method according to claims 1-5, characterized in that: The method comprises the following steps: dispersing indole, α-trifluoromethyl diazonium sulfonium salt, rhodium catalyst and base in an organic solvent, and reacting at -50 to 80° C. in an argon or nitrogen atmosphere.

7. The method according to claim 6, characterized in that The reaction time is 2 to 48 hours. After the reaction is completed, the target product is obtained by extraction, filtration, drying and column chromatography separation.

8. Application of the method according to any one of claims 1 to 7 in the field of pharmaceutical synthesis.

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