A synthetic method and application of a 3-trifluoromethylquinoline compound

Abstract

This invention discloses a method for preparing a 3-trifluoromethylquinoline compound, belonging to the field of organic synthesis. The method involves mixing an organic solvent, a rhodium catalyst, an indole compound, a base, and an α-trifluoromethyldiazosulfonate compound, resulting in a single-carbon atom insertion and ring-expansion reaction to obtain the 3-trifluoromethylquinoline compound. The reactants, catalyst, base, and solvent used in this invention are simple, readily available, and widely sourced, and the operation is convenient. It possesses advantages such as high atom economy and simple process, and has significant application value in the field of drug synthesis.

Description

Technical Field

[0001] This invention relates to a method for preparing 3-trifluoromethylquinoline compounds, belonging to the field of organic synthesis. Background Technology

[0002] Fluorine has a small atomic radius, low orbital energy, and high electronegativity. Therefore, introducing fluorine atoms or fluorine-containing groups into organic compounds does not cause changes in steric hindrance. However, its inductive, pseudo-effect, blocking, lipophilic, and hydrogen bonding effects can significantly alter the physicochemical properties and biological activities of the molecule. Trifluoromethyl groups, as important fluorine-containing groups, are widely used in biomedicine, agrochemicals, and materials science, for example, in drugs such as celecoxib, efavirenz, and etofenamate, and pesticides such as picoxystrobin and fluazinam. However, natural products containing trifluoromethyl groups are extremely rare. Therefore, developing corresponding synthetic methods to introduce trifluoromethyl groups into molecules to enhance their biological activity is a significant undertaking.

[0003] Furthermore, quinoline compounds, as an important backbone, are widely present in drug molecules. Quinoline active functional groups are crucial building blocks for new drug development, serving as structural nuclei or pharmacophores for many innovative drugs and natural products. Quinoline derivatives possess a variety of significant biological activities. Currently reported synthetic methods for 3-trifluoromethylquinoline mainly involve the coupling reaction of sodium trifluoromethanesulfinate or (trifluoromethyl)trimethylsilane with 3-quinoline boric acid. However, most of these methods rely on pre-functionalized substrates and require additional chemical oxidants or high-temperature conditions. Achieving one-pot synthesis of 3-trifluoromethylquinoline compounds using readily available starting materials remains challenging. Therefore, exploring a simpler method for one-step synthesis of 3-trifluoromethylquinoline compounds based on readily available commercial starting materials is of great significance in both organic chemistry and medicinal chemistry. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a method for preparing 3-trifluoromethylquinoline compounds. This method uses readily available and simple raw materials, involves a one-step reaction, and is characterized by low cost, high yield, simple process, and high atom economy.

[0005] This invention utilizes readily available indole compounds and α-trifluoromethyldiazonium sulfonate as raw materials to prepare 3-trifluoromethylquinoline compounds in an organic solvent under the action of a rhodium catalyst and a base. The invention is characterized by: adding an indole compound, α-trifluoromethyldiazonium sulfonate, a rhodium catalyst, and a base to an organic solvent, stirring at a reaction temperature of -50 to 80°C for 2 to 48 hours under an argon or nitrogen atmosphere, and then purifying the mixture by column chromatography to obtain the 3-trifluoromethylquinoline compounds.

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

[0007]

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

[0009] In this invention, the rhodium catalyst is any one of bis[(α,α,α′,α′-tetramethyl-1,3-phenylpropionic acid)rhodium], dipolyrhodium acetate, dipolytrifluoroacetate rhodium, tetracaprolactam dirhodium, tetra(triphenylacetic acid) dirhodium, and dipolyoctanoate rhodium.

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

[0011] This invention also provides the application of this technology in the preparation of drug derivatives of naproxen, ibuprofen, isocolic acid, estradiol, indomethacin, vitamin E, raputimonoindole, and verticillatine B, as well as adapalene drug analogues. Attached Figure Description

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

[0013] Figure 2 The proton NMR 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 nuclear magnetic resonance fluorine spectrum of compound 1 obtained in Example 1. Detailed Implementation

[0016] This invention provides 3,3-trifluoromethylquinoline compounds having the structure shown in Formula I:

[0017]

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

[0019] The 3-trifluoromethylquinoline compounds provided by this invention contain quinoline active functional groups with potential biological activity. These groups serve as the structural core or pharmacophore for many innovative drugs and natural products, which is beneficial 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-trifluoromethyldiazosulfonate as raw materials, 3-trifluoromethylquinoline compounds are prepared in an organic solvent under the action of a rhodium catalyst and a base.

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

[0022]

[0023] Among them, R 2 ~R 5 Selected from H, methyl, methoxy, acetoxy, amino-tert-butoxycarbonyl, phenyl, ester, nitro, halogen, R 1 Selected from methyl and ethyl. The reaction formula for the 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-trifluoromethyldiazosulfonium salt compound, and compound 3 is a 3-trifluoromethylquinoline compound.

[0026] In this invention, the rhodium catalyst is any one of bis[(α,α,α′,α′-tetramethyl-1,3-phenylpropionic acid)rhodium], dipolyrhodium acetate, dipolytrifluoroacetate rhodium, tetracaprolactam dirhodium, tetra(triphenylacetic acid) dirhodium, and dipolyoctanoate rhodium.

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

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

[0029] In this invention, the organic solvent is any one of dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, benzene, and toluene. This invention does not have a particular limitation on the amount of organic solvent used, as long as it is sufficient to dissolve the reaction raw materials. In the embodiments of this invention, the preferred ratio of the indole compound to the organic solvent is 1 mmol: 10-30 mL, more preferably 1 mmol: 20 mL.

[0030] The present invention does not impose any particular limitation on the mixing order of indole compounds, α-trifluoromethyl diazosulfonium salt compounds, base compounds, rhodium catalysts and organic solvents, and the mixing order can be arbitrary.

[0031] In this invention, the temperature at which the single-carbon atom insertion and ring-expansion reaction occurs is preferably -50 to 80°C, more preferably -20 to 50°C; and the time at which the single-carbon atom insertion and ring-expansion reaction occurs 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 from the reaction to room temperature, and then performs column chromatography to remove the solvent from the solution obtained from the column chromatography, thereby obtaining the 3-trifluoromethylquinoline compound.

[0033] The present invention does not impose any particular limitation on the cooling rate, and conventional cooling methods, such as natural cooling, can be used.

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

[0035] This invention also provides the application of this technology in the preparation of drug derivatives of naproxen, ibuprofen, isocolic acid, estradiol, indomethacin, vitamin E, raputimonoindole B and verticillatine B and adapalene drug analogues.

[0036] The following detailed description of the 3-trifluoromethylquinoline compounds and their preparation methods provided by the present invention, with reference to specific examples, should not be construed as limiting the scope of protection of the present invention.

[0037] Example 1

[0038]

[0039] 5-Methyl-6-bromoindole (0.2 mmol), α-trifluoromethyldiazosulfonium salt (0.6 mmol), [(α,α,α′,α′-tetramethyl-1,3-phenylenediol)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 flask and reacted at 0 °C for 60 min under an argon or nitrogen atmosphere. After the reaction was completed, the mixture was evaporated to dryness and 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 column chromatography solution to obtain a yellow solid with a yield of 40.5 mg, a yield of 70%, and a melting point of 79.9–82.4 °C.

[0040] The above-mentioned yellow solid was characterized by single-crystal X-ray diffraction, and the results are as follows: Figure 1 As shown. The above yellow solid was characterized by NMR, and the results are as follows. Figures 2-3 As shown, where Figure 2 This is the proton NMR spectrum. Figure 3 This is a carbon NMR spectrum. Figure 4 The fluorine NMR spectrum is shown below.

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

[0048] The above-mentioned yellow solid was characterized by NMR, and the results are as follows: Figures 1-3 As shown, where Figure 1 This is the proton NMR spectrum. Figure 2 This is a carbon NMR spectrum. Figure 3 The nuclear magnetic resonance fluorine spectrum has the following data:

[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] In Example 1, 5-methyl-6-bromoindole was replaced with 4-methylindole, and other conditions remained the same as in Example 1. 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 NMR, and the specific results 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] In Example 1, 5-methyl-6-bromoindole was replaced with 4-methoxyindole, and other conditions remained the same as in Example 1. 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 NMR, and the specific results 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] Replacing 5-methyl-6-bromoindole in Example 1 with 4-acetoxyindole yielded 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 results 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] In Example 1, 5-methyl-6-bromoindole was replaced with 4-aminotert-butoxycarbonylindole, and other conditions remained the same as in Example 1. 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 results 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] In Example 1, 5-methyl-6-bromoindole was replaced with 4-chloroindole, and other conditions remained the same as in Example 1. 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 NMR, and the specific results 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] In Example 1, 5-methyl-6-bromoindole was replaced with 4-nitroindole, and other conditions remained the same as in Example 1. 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 results 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] In Example 1, 5-methyl-6-bromoindole was replaced with 5-ethylindole, and other conditions remained the same as in Example 1. A brown liquid was finally obtained, with a yield of 36.0 mg and a yield of 80%. The above yellow liquid was characterized by NMR, and the specific results are 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] In Example 1, 5-methyl-6-bromoindole was replaced with 5-benzyloxyindole, and other conditions remained the same as in Example 1. 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 results 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] Example 11

[0110]

[0111] Replacing 5-methyl-6-bromoindole in Example 1 with 5-acetamidoindole yielded 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 NMR, and the specific results 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] In Example 1, 5-methyl-6-bromoindole was replaced with 4-aminotert-butoxycarbonylindole, and other conditions remained the same as in Example 1. 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 NMR, and the specific results 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] Example 13

[0124]

[0125] In Example 1, 5-methyl-6-bromoindole was replaced with methyl 5-carboxylate indole, and other conditions remained the same as in Example 1. 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 NMR, and the specific results 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] Example 14

[0131]

[0132] In Example 1, 5-methyl-6-bromoindole was replaced with 5-chloroindole, and other conditions remained the same as in Example 1. A white solid was finally obtained with a yield of 37.4 mg, representing 81% of the total yield, and a melting point of 68.0–69.4 °C. The white solid was characterized by NMR, and the specific results 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] Example 15

[0138]

[0139] In Example 1, 5-methyl-6-bromoindole was replaced with 6-methylindole, and other conditions remained the same as in Example 1. 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 NMR, and the specific results 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] In Example 1, 5-methyl-6-bromoindole was replaced with 6-benzyloxyindole, and other conditions remained the same as in Example 1. A white solid was obtained with a yield of 48.5 mg, representing 80% of the total yield, and a melting point of 96.8–98.0 °C. The white solid was characterized by NMR, and the specific results 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] Example 17

[0152]

[0153] In Example 1, 5-methyl-6-bromoindole was replaced with methyl 6-carboxylate indole, and other conditions remained the same as in Example 1. 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 NMR, and the specific results 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] Example 18

[0159]

[0160] In Example 1, 5-methyl-6-bromoindole was replaced with ethyl 6-carboxylate indole, and other conditions remained the same as in Example 1. A yellow solid was 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 NMR, and the specific results 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] Example 19

[0167]

[0168] In Example 1, 5-methyl-6-bromoindole was replaced with 3-iodo-8-chlorotryptone, and other conditions were the same as in Example 1. 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 results 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] Example 20

[0174]

[0175] In Example 1, 5-methyl-6-bromoindole was replaced with 6-chloroindole, and other conditions remained the same as in Example 1. 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 NMR, and the specific results 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] Example 21

[0181]

[0182] In Example 1, 5-methyl-6-bromoindole was replaced with 6-iodoindole, and other conditions remained the same as in Example 1. 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 results 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] Example 22

[0188]

[0189] In Example 1, 5-methyl-6-bromoindole was replaced with 7-methylindole, and other conditions remained the same as in Example 1. A yellow liquid was finally obtained, with a yield of 30.8 mg and a yield of 73%. The above yellow solid was characterized by NMR, and the specific results are 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] Example 23

[0195]

[0196] In Example 1, 5-methyl-6-bromoindole was replaced with 7-methoxyindole, and other conditions remained the same as in Example 1. 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 results 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] Example 24

[0202]

[0203] In Example 1, 5-methyl-6-bromoindole was replaced with 7-benzyloxyindole, and other conditions remained the same as in Example 1. A yellow solid was 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 NMR, and the specific results 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] Example 25

[0209]

[0210] In Example 1, 5-methyl-6-bromoindole was replaced with 7-fluoroindole, and other conditions remained the same as in Example 1. A white solid was 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 results 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] Example 26

[0216]

[0217] In Example 1, 5-methyl-6-bromoindole was replaced with 7-chloroindole, and other conditions remained the same as in Example 1. 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 NMR, and the specific results 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] Example 27

[0223]

[0224] In Example 1, 5-methyl-6-bromoindole was replaced with bromoindole, and other conditions remained the same as in Example 1. 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 NMR, and the specific results 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) δ146.9 (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] Example 28

[0230]

[0231] In Example 1, 5-methyl-6-bromoindole was replaced with 4,6-dimethoxyindole, and other conditions remained the same as in Example 1. 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 results 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] Example 29

[0237]

[0238] In Example 1, 5-methyl-6-bromoindole was replaced with methyl 4-bromo-6-carboxylate indole, and other conditions remained the same as in Example 1. 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 NMR, and the specific results 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] Example 30

[0244]

[0245] In Example 1, 5-methyl-6-bromoindole was replaced with 4-bromo-6-chloroindole, and other conditions remained the same as in Example 1. A white solid was 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 NMR, and the specific results 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] Example 31

[0251]

[0252] In Example 1, 5-methyl-6-bromoindole was replaced with 4-bromo-5,7-dimethylindole, and other conditions remained the same as in Example 1. 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 results 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] Example 32

[0258]

[0259] In Example 1, 5-methyl-6-bromoindole was replaced with 5-bromo-7-methylindole, and other conditions remained the same as in Example 1. 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 NMR, and the specific results 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] Example 33

[0265]

[0266] In Example 1, 5-methyl-6-bromoindole was replaced with 5-chloro-6-fluoroindole, and other conditions remained the same as in Example 1. 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 results 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] Example 34

[0272]

[0273] In Example 1, 5-methyl-6-bromoindole was replaced with methyl 6-carboxylate-7-methylindole, and other conditions remained the same as in Example 1. 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 NMR, and the specific results 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] Example 35

[0279]

[0280] In Example 1, 5-methyl-6-bromoindole was replaced with 4-methylindole, and other conditions remained the same as in Example 1. 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 NMR, and the specific results 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] Example 36

[0286]

[0287] In Example 1, 5-methyl-6-bromoindole was replaced with 4-ethylindole, and other conditions remained the same as in Example 1. 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 results 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] Example 37

[0293]

[0294] In Example 1, 5-methyl-6-bromoindole was replaced with 1H,1'H-5,6'-biindole, and other conditions remained the same as in Example 1. 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 results 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] Example 38

[0300]

[0301] In Example 1, 5-methyl-6-bromoindole was replaced with an indole derivative of naproxen, and all other conditions remained the same as in Example 1. A yellow oily substance was finally obtained, with a yield of 61.2 mg and a yield of 72%. The above yellow solid was characterized by NMR, and the specific results 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] Example 39

[0307]

[0308] In Example 1, 5-methyl-6-bromoindole was replaced with an indole derivative of isocolic acid, and other conditions remained the same as in Example 1. 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 results 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] Example 40

[0314]

[0315] In Example 1, 5-methyl-6-bromoindole was replaced with an indole derivative of indomethacin, and other conditions remained the same as in Example 1. A white solid was 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 results 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] Example 41

[0321]

[0322] In Example 1, 5-methyl-6-bromoindole was replaced with an indole derivative of vitamin E, and all other conditions remained the same as in Example 1. A brown oily substance was finally obtained, with a yield of 79.2 mg and a yield of 65%. The above brown oily substance was characterized by NMR, and the specific results 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] Example 42

[0328]

[0329] In Example 1, 5-methyl-6-bromoindole was replaced with an indole derivative of ibuprofen, and other conditions remained the same as in Example 1. 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 results 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] Example 43

[0336]

[0337] In Example 1, 5-methyl-6-bromoindole was replaced with an indole derivative of estradiol, and all other conditions remained the same as in Example 1. 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 results 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] Example 44

[0343]

[0344] In Example 1, 5-methyl-6-bromoindole was replaced with the natural drug molecule Raputimonoindole B, and other conditions remained the same as in Example 1. A yellow solid was 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 results 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] Example 45

[0350]

[0351] In Example 1, 5-methyl-6-bromoindole was replaced with the natural drug molecule Verticillatine B, and all other conditions remained the same as in Example 1. A yellow solid was 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 results 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] Example 46

[0357]

[0358] (1) To a 20 mL Schlenk tube, add 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). Replace the reaction system with an argon gas system, and then stir the resulting reaction mixture at 60 °C for 8 h. After the reaction has cooled to room temperature, extract the reaction system with saturated brine and dichloromethane. Dry the combined organic phases with anhydrous sodium sulfate. After evaporating the solvent, perform column chromatography on the resulting mixture (eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 20:1 to 5:1). Remove the solvent from the column chromatography solution to obtain intermediate 46-1, a yellow solid with a yield of 507.2 mg, which is 71%.

[0359] (2) The above intermediate 46-1 (0.2 mmol), α-trifluoromethyldiazonium sulfonium salt (0.6 mmol), [(α,α,α′,α′-tetramethyl-1,3-phenylenediamine)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 flask 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 column chromatography solution to obtain the target product 46-2, a white solid with a yield of 56.8 mg, a yield of 65%, and a melting point of 193.1–193.5 °C. The above white solid was characterized by NMR, and the specific results 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 a 3-trifluoromethylquinoline compound, characterized in that: An organic solvent, a rhodium catalyst, an indole compound of formula (I), a base, and an α-trifluoromethyldiazosulfonium salt compound of formula (II) are mixed to undergo a single-carbon atom insertion and ring expansion reaction to obtain the 3-trifluoromethylquinoline compound shown in formula (III). Formula I, Formula II, Formula III Among them, R 1 ~R 5 Selected from H, methyl, ethyl, methoxy, acetoxy, tert-butoxycarbonyl, phenyl, nitro, and 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-phenylpropionic acid)rhodium], dipolyacetate rhodium, dipolytrifluoroacetate rhodium, tetracaprolactam dirhodium, tetra(triphenylacetic acid) dirhodium, and dipolyoctanoate rhodium.

3. The method for preparing 3-trifluoromethylquinoline compounds according to claim 1, characterized in that: The alkali 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 diazosulfonium salt compound, the base, and the rhodium catalyst is 1:(1-4):(1-4):(0.01-0.05).

6. The method according to any one of claims 1-5, characterized in that, The method involves dispersing indole, α-trifluoromethyl diazosulfonium salt, rhodium catalyst, and base in an organic solvent and reacting them at -50 to 80°C under 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.

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