Trifluoromethyl substituted indolinone compound as well as synthesis method and application thereof

Abstract

The invention discloses trifluoromethyl substituted indolinone compounds as well as a synthesis method and application thereof, and belongs to the technical field of medicine synthesis. An N-phenylpyridine-2-amine compound and a trifluoromethyl imine sulfoxide ylide compound are used as initial raw materials, the trifluoromethyl substituted indolinone compound is synthesized through a one-pot cascade reaction, and the process is simple and efficient; raw materials are cheap and easily available, reaction conditions are mild, and operation is simple; the substrate is wide in application range, and the functional group tolerance is good. An anti-cancer cell activity test verifies that the compound provided by the invention has the activity of obviously inhibiting proliferation of three cancer cells, namely Hela, A549 and HCT-116, so that the compound provided by the invention has the anti-cancer activity on cervical cancer, lung cancer and colon cancer, has potential medicinal value and provides a new structural unit for drug screening.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drugs and organic synthesis, and particularly relates to trifluoromethyl-substituted indolinone compounds, their synthesis methods and applications. Background Art

[0002] Indole is one of the most common nitrogen heterocyclic skeletons in drugs and is the core skeleton of many natural products and biomolecules, having antibacterial and anti-tumor activities. 2,2-Disubstituted indolin-3-one is widespread in natural alkaloids, clinical drugs and commercial dyes and is also an important raw material for synthesizing pesticides, fluorescent probes and solar cell materials. On the other hand, trifluoromethyl is one of the advantageous structural units in new drug design. Introducing trifluoromethyl into an organic compound molecule often affects the permeability, lipophilicity and metabolic stability of the parent compound, etc., thus increasing the possibility of discovering new lead compounds. In view of the importance of the indolinone structural skeleton and trifluoromethyl, trifluoromethyl-substituted indolinone compounds may have more significant biological activities and physicochemical properties and have good application prospects in aspects such as drug discovery and new material development.

[0003] At present, reports on the synthesis methods of trifluoromethyl-substituted indolinone compounds are very limited, and there are also problems such as difficult availability of raw materials, cumbersome steps, poor atom economy, low efficiency and harsh reaction conditions.

[0004] Therefore, synthesizing trifluoromethyl-substituted indolinone compounds, studying their biological activities and medicinal values, and developing a green, efficient and highly atom-economic new method for synthesizing such compounds starting from simple and easily available raw materials via simple steps have important theoretical significance and application value. Summary of the Invention

[0005] In order to solve the problems existing in the prior art, one of the purposes of the present invention is to provide trifluoromethyl-substituted indolinone compounds, and these compounds have anti-cancer activities. Another purpose of the present invention is to provide the application of trifluoromethyl-substituted indolinone compounds in the preparation of anti-cancer drugs. The third purpose of the present invention is to provide a pharmaceutical composition for treating cervical cancer, colon cancer and / or lung cancer, and its active ingredient is the trifluoromethyl-substituted indolinone compound provided by the present invention. The fourth purpose of the present invention is to provide a synthesis method of trifluoromethyl-substituted indolinone compounds.

[0006] In order to achieve the above purposes, the technical scheme adopted by the present invention is as follows: Trifluoromethyl-substituted indolinone compounds, the general structural formula of which is: Wherein: R 1 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, phenyl or halogen; R2 Selected from hydrogen, C 1-4 alkyl or halogen; R 3 is selected from C 1-4 linear alkyl, phenyl-substituted C 1-4 linear alkyl, phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is C 1-4 alkyl, C 1-4 alkoxy or halogen.

[0007] Furthermore, in the above general formula structure, in the most preferred case, it is selected from the following specific structures:

[0008]

[0009] The present invention designs experiments to verify that the compounds provided by the present invention have the activity of inhibiting the proliferation of three cancer cells, namely Hela, A549, and HCT-116, suggesting that the compounds of the present invention can be used as the active ingredients of drugs for treating cancers such as cervical cancer, lung cancer, and colon cancer. In particular, the above-mentioned preferred compounds can significantly inhibit the growth and proliferation of Hela, A549, and HCT-116, suggesting that these compounds, as the active ingredients of anti-cancer drugs, have the effects of preventing, treating, and inhibiting the progression and deterioration of cervical cancer, lung cancer, and colon cancer.

[0010] Use of the foregoing trifluoromethyl-substituted indolinone compounds in the preparation of anti-cancer drugs, wherein the anti-cancer drugs are for treating cervical cancer, lung cancer, and / or colon cancer.

[0011] A pharmaceutical composition for treating cervical cancer, lung cancer, and / or colon cancer, the active ingredient of which comprises the foregoing trifluoromethyl-substituted indolinone compounds.

[0012] The present invention also provides a synthesis method of the above-mentioned trifluoromethyl-substituted indolinone compounds, and the technical solution adopted is as follows:

[0013] A synthesis method of trifluoromethyl-substituted indolinone compound 3, comprising the following steps: mixing an N-phenylpyridin-2-amine compound 1, a trifluoromethylsulfoximine ylide compound 2, a rhodium catalyst, an additive, and an organic solvent, and heating and reacting in an oxygen-containing atmosphere to obtain a trifluoromethyl-substituted indolinone compound 3; the reaction equation is expressed as:

[0014]

[0015] Wherein: R 1 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, phenyl or halogen; R 2 is selected from hydrogen, C 1-4 alkyl or halogen; R 3 is selected from C 1-4 linear alkyl, phenyl-substituted C1-4 A chain alkyl group, a phenyl group or a substituted phenyl group, and the substituent on the benzene ring of the substituted phenyl group is C 1-4 alkyl group, C 1-4 alkoxy group or halogen.

[0016] Furthermore, in the above synthesis method, the additive is selected from a mixture of silver hexafluoroantimonate and a copper salt, and the copper salt is copper acetate, copper acetate monohydrate, copper chloride or copper bromide.

[0017] Furthermore, in the above synthesis method, the rhodium catalyst is dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer ([RhCp*Cl2]2).

[0018] Furthermore, in the above synthesis method, the organic solvent is selected from trifluoroethanol or a mixture of trifluoroethanol and ethanol.

[0019] Furthermore, in the above synthesis method, the molar ratio of compound 1, compound 2, rhodium catalyst, silver hexafluoroantimonate and copper salt is 1 - 1.5:1 - 3:0.02 - 0.07:0.1 - 1:0.1 - 2.

[0020] Furthermore, in the above synthesis method, the reaction temperature is 30 - 90 °C; the preferred reaction temperature is 50 °C.

[0021] Furthermore, in the above synthesis method, the oxygen-containing atmosphere is selected from air or an oxygen atmosphere.

[0022] Advantages of the invention:

[0023] (1) For the trifluoromethyl-substituted indolinone compounds provided by the present invention, by screening compounds with various substituents and verifying through anti-cancer cell activity tests, the compounds provided by the present invention have obvious activity in inhibiting the proliferation of three cancer cells, namely Hela, A549 and HCT-116, indicating that the compounds of the present invention have anti-cancer activity against cervical cancer, lung cancer and colon cancer, have potential medicinal value, and provide a new structural unit for drug screening;

[0024] (2) For the synthesis method provided by the present invention, using N-phenylpyridin-2-amine compounds and trifluoromethyl imine sulfoxide ylides as starting materials, trifluoromethyl-substituted indolinone compounds are synthesized through a one-pot tandem reaction, and the process is simple and efficient;

[0025] (3) The synthesis method provided by the present invention has cheap and easily available raw materials, mild reaction conditions, simple operation, wide substrate applicability and good functional group tolerance. Description of the drawings

[0026] Figure 1X-ray single crystal diffraction pattern of compound 3a in Example 1. Detailed implementation mode

[0027] The above content of the present invention will be further described in detail below through examples, but it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. Any technology implemented based on the above content of the present invention belongs to the scope of the present invention.

[0028] Example 1

[0029] Compound 1a, additive 1, additive 2, rhodium catalyst, compound 2a and solvent were successively added to a 15 mL reaction tube, and then the reaction tube was sealed and placed in an oil bath for heating and stirring reaction. After the reaction was completed, it was cooled to room temperature, filtered through a diatomaceous earth pad and concentrated under reduced pressure, and separated by a silica gel column (petroleum ether / dichloromethane = 1 / 1) to obtain a yellow solid product 3a; the reaction equation is shown as follows:

[0030]

[0031] By changing the reaction conditions such as reaction additives, temperature, material ratio, gas atmosphere and organic solvents, a series of results were obtained, as shown in Table 1.

[0032] Table 1 Synthesis of 3a under different conditions a

[0033]

[0034]

[0035] Example 2

[0036]

[0037] 1a (34.0 mg, 0.2 mmol), silver hexafluoroantimonate (13.7 mg, 0.04 mmol), cupric acetate anhydrous (18.2 mg, 0.1 mmol), [RhCp*Cl2]2 (4.9 mg, 0.008 mmol), 2a (105.3 mg, 0.4 mmol), trifluoroethanol (1.5 mL) and absolute ethanol (0.5 mL) were successively added to a 15 mL pressure-resistant tube. After the reaction tube was sealed, it was evacuated and filled with oxygen, and placed in an oil bath at 50 °C for reaction for 12 h. After the reaction was completed, the reaction system was cooled to room temperature, filtered through a diatomaceous earth pad and concentrated under reduced pressure, and separated by a silica gel column (petroleum ether / dichloromethane = 1 / 1) to obtain a yellow solid product 3a (48.8 mg, 66%). The characterization data of this compound are as follows: 11H NMR (400 MHz, CDCl3): δ 8.45 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.64 - 7.60 (m, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.11 - 7.02 (m, 4H), 6.79 (t, J = 7.6 Hz, 1H), 6.57 (d, J = 7.6 Hz, 2H), 5.02 (s, 1H). 13 13C NMR (150 MHz, CDCl3): δ 192.0, 156.8, 151.5, 148.7, 141.6, 138.4, 138.2, 129.4, 125.0, 122.2 (q, 1 J C-F = 289.1 Hz), 121.7, 121.3, 120.9, 120.7, 117.7, 116.4, 114.5, 81.3 (q, 2 J C-F = 28.4 Hz). 19 19F NMR (376 MHz, CDCl3): δ -75.92 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 20 H 14 F3N3NaO 392.0981; Found 392.0976.

[0038] Example 3

[0039] According to the method and steps of Example 2 a,b , by changing Reactant 1 and Reactant 2, various trifluoromethyl-substituted indolinone compounds 3 can be synthesized. The specific results are as follows:

[0040]

[0041]

[0042] Characterization data of representative product are as follows: 5-Ethyl-2-(phenylamino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3b): 11H NMR (600 MHz, CDCl3): δ 8.42 - 8.41 (m, 1H), 7.60 - 7.58 (m, 2H), 7.52 - 7.47 (m, 2H), 7.29 (d, J = 7.8 Hz, 1H), 7.05 - 7.01 (m, 3H), 6.77 (t, J = 7.2 Hz, 1H), 6.55 (d, J = 7.8 Hz, 2H), 5.04 (s, 1H), 2.67 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.8 Hz, 3H). 13 13C NMR (150 MHz, CDCl3): δ 192.1, 155.2, 151.8, 148.5, 141.7, 138.8, 138.1, 138.0, 129.3, 123.2, 122.3 (q, 1 J C-F = 288.5 Hz), 121.2, 121.1, 120.4, 117.1, 116.4, 114.8, 81.5 (q, 2 J C-F = 27.0 Hz), 28.0, 15.3. 19 19F NMR (565 MHz, CDCl3): δ -75.88 (s). HRMS (ESI) m / z: [M + Na] + Calcd for C 22 H 18 F3N3NaO 420.1294; Found 420.1290.

[0043] 5-Methoxy-2-(phenylamino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3c): 1 1H NMR (600 MHz, CDCl3): δ 8.39 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.60 - 7.57 (m, 1H), 7.29 - 7.27 (m, 2H), 7.18 (d, J = 2.4 Hz, 1H), 7.04 - 7.01 (m, 3H), 6.77 (t, J = 7.8 Hz, 1H), 6.54 (d, J = 7.8 Hz, 2H), 5.02 (s, 1H), 3.83 (s, 3H). 13 13C NMR (150 MHz, CDCl3): δ 192.2, 155.0, 152.0, 151.8, 148.4, 141.6, 138.0, 129.3, 128.2, 122.3 (q, 1 JC-F = 288.9 Hz), 121.5, 121.2, 120.1, 116.8, 116.6, 116.3, 104.9, 81.7 (q, 2 J C-F = 27.8 Hz), 55.9. 19 19F NMR (565 MHz, CDCl3): δ -75.97 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 21 H 16 F3N3NaO2 422.1087; Found 422.1084.

[0044] 5-Fluoro-2-(phenylamino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3d) 1 1H NMR (400 MHz, CDCl3): δ 8.44 - 8.42 (m, 1H), 7.65 - 7.61 (m, 2H), 7.41 - 7.34 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 7.11 - 7.03 (m, 3H), 6.80 (t, J = 7.6 Hz, 1H), 6.56 - 6.54 (m, 2H), 4.98 (s, 1H). 13 13C NMR (100 MHz, CDCl3): δ 191.8 (d, 4 J C-F = 3.9 Hz), 157.6 (d, 1 J C-F = 242.4 Hz), 153.3, 151.4, 148.5, 141.4, 138.3, 129.5, 126.0 (d, 2 J C-F = 24.5 Hz), 122.1 (q, 1 J C-F = 289.1 Hz), 121.5, 120.9, 117.4, 116.7 (d, 3 J C-F = 7.5 Hz), 116.3, 109.9 (d, 2 J C-F = 23.1 Hz), 81.8 (q, 2 J C-F = 28.1 Hz). 1919F NMR (376 MHz, CDCl3): δ -75.99 (s), -120.66 (td, J1 = 7.9 Hz, J2 = 4.1 Hz). HRMS (ESI) m / z: [M+Na] + Calcd for C 20 H 13 F4N3NaO 410.0887; Found 410.0886.

[0045] 5-Chloro-2-(phenylamino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3e) 1 1H NMR (600 MHz, CDCl3): δ 8.44 (dd, J1 = 4.8 Hz, J2 = 1.8 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.66 - 7.63 (m, 1H), 7.58 - 7.54 (m, 2H), 7.28 (d, J = 8.4 Hz, 1H), 7.12 (dd, J1 = 7.2 Hz, J2 = 4.8 Hz, 1H), 7.07 - 7.05 (m, 2H), 6.81 (t, J = 7.2 Hz, 1H), 6.55 (d, J = 7.8 Hz, 2H), 4.97 (s, 1H). 13 13C NMR (100 MHz, CDCl3): δ 190.7, 157.2, 151.0, 148.8, 145.1, 141.5, 138.5, 129.5, 125.8, 122.5, 122.0 (q, 1 J C-F = 288.9 Hz), 121.53, 121.49, 119.0, 118.1, 116.3, 114.8, 81.6 (q, 2 J C-F = 27.9 Hz). 19 19F NMR (376 MHz, CDCl3): δ -75.95 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 20 H 13 ClF3N3NaO 426.0591; Found 426.0594.

[0046] 5-Bromo-2-(phenylamino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3f) 11H NMR (600 MHz, CDCl3): δ 8.44 (dd, J1 = 5.4 Hz, J2 = 1.2 Hz, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.68 (dd, J1 = 9.0 Hz, J2 = 2.4 Hz, 1H), 7.64 (td, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.12 (dd, J1 = 7.8 Hz, J2 = 5.4 Hz, 1H), 7.06 (t, J = 8.4 Hz, 2H), 6.81 (t, J = 7.2 Hz, 1H), 6.55 (d, J = 7.8 Hz, 2H), 4.97 (br s, 1H). 13 13C NMR (100 MHz, CDCl3): δ 190.9, 155.6, 151.1, 148.7, 141.4, 140.8, 138.4, 129.5, 127.2, 122.2, 122.0 (q, 1 J C-F = 288.7 Hz), 121.5, 121.2, 117.8, 116.6, 116.3, 114.1, 81.6 (q, 2 J C-F = 28.1 Hz). 19 19F NMR (565 MHz, CDCl3): δ -75.94 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 20 H 13 BrF3N3NaO4 70.0086; Found 470.0089.

[0047] 6-Methyl-2-(phenylamino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3g) 1 1H NMR (400 MHz, CDCl3): δ 8.46 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.31 (s, 1H), 7.27 (d, J = 9.2 Hz, 1H), 7.11 - 7.08 (m, 1H), 7.04 (t, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 5.00 (s, 1H), 2.42 (s, 3H). 1313C NMR (100 MHz, CDCl3): δ 191.1, 157.2, 151.5, 150.6, 148.7, 141.7, 138.3, 129.4, 124.8, 123.4, 122.3 (q, 1 J C-F = 288.2 Hz), 121.2, 120.9, 118.6, 118.0, 116.3, 114.4, 81.5 (q, 2 J C-F = 28.4 Hz), 23.0. 19 19F NMR (376 MHz, CDCl3): δ -76.02 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 21 H 16 F3N3NaO 406.1138; Found 406.1132.

[0048] 6-Chloro-2-(phenylamino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3h) 1 1H NMR (600 MHz, CDCl3): δ 8.49 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H), 7.68 - 7.65 (m, 2H), 7.58 (d, J = 1.8 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.16 - 7.14 (m, 1H), 7.09 - 7.06 (m, 2H), 7.03 (dd, J1 = 7.8 Hz, J2 = 1.2 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 7.8 Hz, 2H), 4.97 (s, 1H). 13 13C NMR (100 MHz, CDCl3): δ 190.7, 157.2, 151.0, 148.8, 145.1, 141.5, 138.5, 129.5, 125.8, 122.5, 122.0 (q, 1 J C-F = 288.9 Hz), 121.53, 121.49, 119.0, 118.1, 116.3, 114.8, 81.6 (q, 2 J C-F = 27.9 Hz). 19 19F NMR (565 MHz, CDCl3): δ -76.00 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C20 H 13 ClF3N3NaO 426.0591; Found 426.0596.

[0049] 6-Bromo-2-(phenylamino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3i) 1 1H NMR (400 MHz, CDCl3): δ 8.49 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.66 (td, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.18 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 7.16 - 7.13 (m, 1H), 7.10 - 7.06 (m, 2H), 6.82 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 7.6 Hz, 2H), 4.98 (s, 1H). 13 13C NMR (100 MHz, CDCl3): δ 191.0, 157.1, 150.9, 148.8, 141.4, 138.5, 134.2, 129.5, 125.7, 125.3, 122.0 (q, 1 J C-F = 288.6 Hz), 121.53, 121.52, 119.3, 118.1, 117.8, 116.3, 81.5 (q, 2 J C-F = 28.0 Hz). 19 19F NMR (376 MHz, CDCl3): δ -75.98 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 20 H 13 BrF3N3NaO 470.0086; Found 470.0089.

[0050] 6-Phenyl-2-(phenylamino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3j) 11H NMR (400 MHz, CDCl3): δ 8.47 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.65 - 7.61 (m, 3H), 7.47 - 7.38 (m, 3H), 7.33 - 7.24 (m, 2H), 7.11 - 7.04 (m, 3H), 6.80 (t, J = 7.2 Hz, 1H), 6.62 (d, J = 8.0 Hz, 2H), 5.05 (s, 1H). 13 13C NMR (100 MHz, CDCl3): δ 191.4, 157.2, 151.6, 151.5, 148.8, 141.7, 140.0, 138.3, 129.4, 129.0, 128.9, 127.6, 125.3, 122.3 (q, 1 J C-F = 288.6 Hz), 121.4, 121.3, 121.0, 119.6, 117.9, 116.5, 112.7, 81.7 (q, 2 J C-F = 27.8 Hz). 19 19F NMR (376 MHz, CDCl3): δ -75.86 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 26 H 18 F3N3NaO 468.1294; Found 468.1290.

[0051] 4-Fluoro-2-(phenylamino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3k) 1 1H NMR (600 MHz, CDCl3): δ 8.48 - 8.47 (m, 1H), 7.67 - 7.64 (m, 1H), 7.58 - 7.54 (m, 1H), 7.28 - 7.25 (m, 2H), 7.16 - 7.13 (m, 1H), 7.09 - 7.07 (m, 2H), 6.82 (t, J = 7.2 Hz, 1H), 6.66 (t, J = 8.4 Hz, 1H), 6.63 - 6.61 (m, 2H), 4.98 (s, 1H). 13 13C NMR (150 MHz, CDCl3): δ 188.0, 158.9 (d, 1 J C-F = 262.2 Hz), 157.4 (d, 3 ​C-F = 5.1 Hz), 151.0, 148.8, 141.5, 140.1 (d, 3 J C-F = 10.1 Hz), 138.5, 129.5, 122.0 (q, 1 J C-F = 288.0 Hz), 121.6, 121.5, 118.5, 116.5, 110.0 (d, 4 J C-F = 2.7 Hz), 109.5 (d, 2 J C-F = 17.3 Hz), 107.9 (d, 2 J C-F = 18.0 Hz), 81.6 (q, 2 J C-F = 28.5 Hz). 19 F NMR (565 MHz, CDCl3): δ -75.99 (s), -109.78--109.81 (m). HRMS (ESI) m / z: [M+Na] + Calcd for C 20 H 13 F4N3NaO 410.0887; Found 410.0886.

[0052] 1-(4-Methylpyridin-2-yl)-2-(phenylamino)-2-(trifluoromethyl)indolin-3-one (3l) 1 H NMR (400 MHz, CDCl3): δ 8.31 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.62 - 7.58 (m, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.09 (s, 1H), 7.07 - 7.01 (m, 3H), 6.93 (d, J = 5.2 Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.60 (d, J = 8.0 Hz, 2H), 5.03 (s, 1H), 2.27 (s, 3H). 13 C NMR (100 MHz, CDCl3): δ 192.1, 157.1, 151.6, 149.7, 148.3, 141.8, 138.4, 129.3, 124.9, 122.24 (q, 1 J C-F= 288.8 Hz), 122.19, 121.5, 121.3, 120.6, 118.3, 116.7, 114.4, 81.3 (q, 2 J C-F = 27.4 Hz), 21.2. 19 19F NMR (376 MHz, CDCl3): δ -75.86 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 21 H 16 F3N3NaO 406.1138; Found 406.1136.

[0053] 2-((4-Ethylphenyl)amino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3m) 1 1H NMR (600 MHz, CDCl3): δ 8.46 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.65 - 7.59 (m, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.10 (dd, J1 = 7.2 Hz, J2 = 4.8 Hz, 1H), 7.04 (t, J = 7.2 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 6.53 (d, J = 8.4 Hz, 2H), 4.94 (s, 1H), 2.45 (q, J = 7.8 Hz, 2H), 1.09 (t, J = 7.8 Hz, 3H). 13 13C NMR (150 MHz, CDCl3): δ 192.3, 156.8, 151.6, 148.6, 139.4, 138.3, 138.2, 137.2, 128.7, 124.9, 122.2 (q, 1 J C-F = 288.5 Hz), 121.6, 120.8, 120.7, 117.8, 116.8, 114.4, 81.5 (q, 2 J C-F = 27.3 Hz), 27.9, 15.5. 19 19F NMR (565 MHz, CDCl3): δ -75.90 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 22 H 18 F3N3NaO 420.1294; Found 420.1284.

[0054] 2-((4-(tert-Butyl)phenyl)amino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one(3n): 1 1H NMR(600 MHz,CDCl3):δ8.46(dd,J1=4.2Hz,J2=1.2Hz,1H),7.74(dd,J1=7.8Hz,J2=0.6Hz,1H),7.64-7.60(m,2H),7.56(d,J=7.8Hz,1H),7.32(d,J=8.4Hz,1H),7.11-7.09(m,1H),7.06-7.03(m,3H),6.53-6.51(m,2H),4.94(s,1H),1.17(s,9H). 13 13C NMR(150 MHz,CDCl3):δ192.3,156.8,151.6,148.6,144.0,139.0,138.4,138.2,126.2,124.9,122.2(q, 1 J C-F =288.8Hz),121.6,120.9,120.7,117.9,116.1,114.4,81.4(q, 2 J C-F =27.8Hz),34.0,31.3. 19 19F NMR(565 MHz,CDCl3):δ-75.94(s).HRMS(ESI)m / z:[M+Na] + Calcd for C 24 H 22 F3N3NaO 448.1607;Found448.1619.

[0055] 2-((4-Methoxyphenyl)amino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one(3o): 11H NMR (400 MHz, CDCl3): δ 8.48 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H), 7.71 - 7.65 (m, 2H), 7.60 - 7.56 (m, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.13 - 7.10 (m, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.67 - 6.64 (m, 2H), 6.62 - 6.59 (m, 2H), 4.99 (s, 1H), 3.64 (s, 3H). 13 13C NMR (150 MHz, CDCl3): δ 192.1, 156.9, 155.0, 151.8, 148.7, 138.3, 138.2, 134.9, 125.0, 122.3 (q, 1 J C-F = 289.2 Hz), 121.6, 120.8, 120.7, 119.9, 117.4, 114.6, 113.9, 82.1 (q, 2 J C-F = 26.6 Hz), 55.4. 19 19F NMR (376 MHz, CDCl3): δ -75.65 (s). HRMS (ESI) m / z: [M + Na] + Calcd for C 21 H 16 F3N3NaO2 422.1087; Found 422.1096.

[0056] 2-((4-Chlorophenyl)amino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3p) 1 1H NMR (600 MHz, CDCl3): δ 8.46 - 8.45 (m, 1H), 7.75 (dd, J1 = 7.8 Hz, J2 = 0.6 Hz, 1H), 7.67 - 7.61 (m, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.13 - 7.11 (m, 1H), 7.07 (t, J = 7.2 Hz, 1H), 7.01 - 6.99 (m, 2H), 6.56 - 6.53 (m, 2H), 5.07 (s, 1H). 1313C NMR (150 MHz, CDCl3): δ 191.6, 156.8, 151.4, 148.8, 140.3, 138.6, 138.3, 129.3, 126.6, 125.1, 122.1 (q, 1 J C-F = 289.1 Hz), 121.9, 121.0, 120.6, 118.2, 117.4, 114.4, 81.3 (q, 2 J C-F = 27.9 Hz). 19 19F NMR (565 MHz, CDCl3): δ -75.83 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 20 H 13 ClF3N3NaO 426.0591; Found 426.0594.

[0057] 2-((4-Bromophenyl)amino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3q)

[0058] 1 1H NMR (400 MHz, CDCl3): δ 8.45 (dd, J1 = 4.8 Hz, J2 = 0.8 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.15 - 7.10 (m, 3H), 7.07 (t, J = 7.2 Hz, 1H), 6.49 (d, J = 8.8 Hz, 2H), 5.08 (s, 1H). 13 13C NMR (100 MHz, CDCl3): δ 191.6, 156.8, 151.4, 148.8, 140.8, 138.6, 138.3, 132.2, 125.1, 122.1 (q, 1 J C-F = 288.8 Hz), 121.9, 121.0, 120.6, 118.5, 117.4, 114.4, 113.9, 81.2 (q, 2 J C-F = 28.0 Hz). 19 19F NMR (376 MHz, CDCl3): δ -75.84 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C20 H 13 BrF3N3NaO 470.0086; Found 470.0087.

[0059] 1-(Pyridin-2-yl)-2-(m-tolylamino)-2-(trifluoromethyl)indolin-3-one(3r): 1 1H NMR (400 MHz, CDCl3): δ 8.46 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.64 - 7.59 (m, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.09 (dd, J1 = 7.2 Hz, J2 = 4.8 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 6.45 (s, 1H), 6.33 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 4.98 (s, 1H), 2.12 (s, 3H). 13 13C NMR (100 MHz, CDCl3): δ 192.2, 156.8, 151.6, 148.6, 141.7, 139.2, 138.4, 138.3, 129.3, 124.8, 122.25, 122.24 (q, 1 J C-F = 289.0 Hz), 121.7, 120.9, 120.7, 117.8, 117.7, 114.4, 113.0, 81.3 (q, 2 J C-F = 28.0 Hz), 21.4. 19 19F NMR (376 MHz, CDCl3): δ -75.94 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 21 H 16 F3N3NaO 406.1138; Found 406.1124.

[0060] 2-((3-Fluorophenyl)amino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one(3s) 11H NMR (600 MHz, CDCl3): δ 8.47 - 8.46 (m, 1H), 7.77 (dd, J1 = 7.8 Hz, J2 = 0.6 Hz, 1H), 7.66 - 7.62 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.13 - 7.11 (m, 1H), 7.09 - 7.06 (m, 1H), 7.01 - 6.97 (m, 1H), 6.51 - 6.48 (m, 1H), 6.36 - 6.34 (m, 1H), 6.32 - 6.30 (m, 1H), 5.13 (s, 1H). 13 13C NMR (100 MHz, CDCl3): δ 191.5, 163.4 (d, 1 J C-F = 243.3 Hz), 156.8, 151.4, 148.8, 143.4 (d, 3 J C-F = 10.5 Hz), 138.6, 138.3, 130.6 (d, 3 J C-F = 9.6 Hz), 125.1, 122.1 (q, 1 J C-F = 288.7 Hz), 122.0, 121.0, 120.5, 117.5, 114.4, 112.1 (d, 4 J C-F = 2.8 Hz), 108.1 (d, 2 J C-F = 21.2 Hz), 103.9 (d, 2 J C-F = 25.9 Hz), 81.0 (q, 2 J C-F = 27.9 Hz). 19 19F NMR (565 MHz, CDCl3): δ -75.89 (s), -111.58--111.63 (m). HRMS (ESI) m / z: [M+Na] + Calcd for C 20 H 13 F4N3NaO 410.0887; Found 410.0884.

[0061] 2-((2-Fluorophenyl)amino)-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3t) 11H NMR (400 MHz, CDCl3): δ 8.43 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.67 - 7.62 (m, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.12 - 7.07 (m, 2H), 6.98 - 6.93 (m, 1H), 6.74 - 6.70 (m, 2H), 6.39 - 6.35 (m, 1H), 5.27 (d, J = 2.8 Hz, 1H). 13 13C NMR (100 MHz, CDCl3): δ 191.8, 157.0, 152.2 (d, 1 J C-F = 239.5 Hz), 151.2, 148.7, 138.5, 138.3, 130.2 (d, 2 J C-F = 10.7 Hz), 125.0, 124.7 (d, 4 J C-F = 3.5 Hz), 122.2 (q, 1 J C-F = 288.8 Hz), 121.9, 121.04, 120.96 (d, 3 J C-F = 7.3 Hz), 120.6, 117.6 (d, J C-F = 1.3 Hz), 115.4 (d, J C-F = 1.8 Hz), 115.1 (d, 2 J C-F = 18.7 Hz), 114.8, 80.6 (q, 2 J C-F = 28.6 Hz). 19 19F NMR (376 MHz, CDCl3): δ -75.95 (s), -133.14 - -133.20 (m). HRMS (ESI) m / z: [M + Na] + Calcd for C 20 H 13 F4N3NaO 410.0887; Found 410.0872.

[0062] 2 - ((4 - (tert - Butyl)phenyl)amino) - 5 - ethyl - 1 - (pyridin - 2 - yl) - 2 - (trifluoromethyl)indolin - 3 - one (3u): 11H NMR (400 MHz, CDCl3): δ 8.43 - 8.41 (m, 1H), 7.61 - 7.53 (m, 3H), 7.47 (dd, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.06 - 7.02 (m, 3H), 6.52 - 6.49 (m, 2H), 4.96 (s, 1H), 2.66 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H), 1.17 (s, 9H). 13 13C NMR (100 MHz, CDCl3): δ 192.4, 155.2, 151.8, 148.5, 143.8, 139.1, 138.7, 138.1, 137.8, 126.2, 123.1, 122.3 (q, 1 J C-F = 288.5 Hz), 121.0, 120.4, 117.4, 116.0, 114.7, 81.6 (q, 2 J = 28.3 Hz), 34.0, 31.3, 28.0, 15.3. 19 19F NMR (565 MHz, CDCl3): δ -75.87 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 26 H 26 F3N3NaO 476.1920; Found 476.1914.

[0063] 2-((4-Bromophenyl)amino)-5-ethyl-1-(pyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3v): 1 1H NMR (400 MHz, CDCl3): δ 8.42 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H), 7.65 - 7.60 (m, 1H), 7.57 (s, 1H), 7.51 - 7.46 (m, 2H), 7.28 (d, J = 8.0 Hz, 1H), 7.14 - 7.11 (m, 2H), 7.09 - 7.05 (m, 1H), 6.49 - 6.45 (m, 2H), 5.09 (s, 1H), 2.67 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H). 1313C NMR (150 MHz, CDCl3): δ 191.7, 155.1, 151.6, 148.6, 140.9, 139.0, 138.22, 138.20, 132.2, 123.3, 122.2 (q, 1 J C-F = 288.8 Hz), 120.9, 120.5, 118.4, 116.9, 114.7, 113.8, 81.4 (q, 2 J = 28.1 Hz), 28.0, 15.2. 19 19F NMR (376 MHz, CDCl3): δ -75.81 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 22 H 17 BrF3N3NaO 498.0399; Found 498.0404.

[0064] 1-(4-Methylpyridin-2-yl)-2-(m-tolylamino)-2-(trifluoromethyl)indolin-3-one (3w) 1 1H NMR (600 MHz, CDCl3): δ 8.32 (d, J = 5.4 Hz, 1H), 7.73 (dd, J1 = 7.8 Hz, J2 = 0.6 Hz, 1H), 7.61 - 7.58 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 7.02 (t, J = 7.2 Hz, 1H), 6.94 (d, J = 4.2 Hz, 1H), 6.91 (t, J = 8.4 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 6.47 (s, 1H), 6.36 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 4.95 (s, 1H), 2.28 (s, 3H), 2.13 (s, 3H). 13 13C NMR (100 MHz, CDCl3): δ 192.2, 157.1, 151.7, 149.6, 148.3, 141.8, 139.1, 138.4, 129.2, 124.8, 122.3, 122.23 (q, 1 J C-F = 289.8 Hz), 122.21, 121.4, 120.6, 118.4, 117.9, 114.3, 113.4, 81.3 (q, 2 J = 28.0 Hz), 21.4, 21.2. 1919F NMR (565 MHz, CDCl3): δ -75.88 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 22 H 18 F3N3NaO 420.1294; Found 420.1291.

[0065] 2-((4-(tert-Butyl)phenyl)amino)-1-(4-methylpyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3x): 1 1H NMR (600 MHz, CDCl3): δ 8.31 (d, J = 5.4 Hz, 1H), 7.73 (dd, J1 = 7.8 Hz, J2 = 0.6 Hz, 1H), 7.61 - 7.58 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 7.06 - 7.02 (m, 3H), 6.93 (d, J = 5.4 Hz, 1H), 6.54 - 6.52 (m, 2H), 4.92 (br s, 1H), 2.28 (s, 3H), 1.18 (s, 9H). 13 13C NMR (100 MHz, CDCl3): δ 192.3, 157.1, 151.7, 149.6, 148.3, 144.0, 139.2, 138.3, 126.2, 124.9, 122.2 (q, 1 J C-F = 288.7 Hz), 122.1, 121.4, 120.7, 118.4, 116.4, 114.3, 81.4 (q, 2 J = 28.2 Hz), 34.0, 31.3, 21.1. 19 19F NMR (565 MHz, CDCl3): δ -75.86 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 25 H 24 F3N3NaO 462.1764; Found 462.1762.

[0066] 2-((4-Bromophenyl)amino)-1-(4-methylpyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3y): 11H NMR (600 MHz, CDCl3): δ 8.31 (d, J = 5.4 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.62 - 7.60 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.16 - 7.14 (m, 2H), 7.08 (s, 1H), 7.05 (t, J = 7.8 Hz, 1H), 6.95 (d, J = 4.8 Hz, 1H), 6.53 - 6.50 (m, 2H), 5.07 (s, 1H), 2.31 (s, 3H). 13 13C NMR (150 MHz, CDCl3): δ 191.6, 157.1, 151.5, 149.8, 148.5, 141.0, 138.6, 132.2, 125.1, 122.3, 122.1 (q, 1 J C-F = 288.9 Hz), 121.7, 120.5, 118.8, 118.1, 114.2, 114.0, 81.2 (q, 2 J = 28.7 Hz), 21.3. 19 19F NMR (565 MHz, CDCl3): δ -75.80 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 21 H 15 BrF3N3NaO 484.0243; Found 484.0249.

[0067] 2-((4-(tert-Butyl)phenyl)amino)-1-(5-chloropyridin-2-yl)-2-(trifluoromethyl)indolin-3-one (3z): 1 1H NMR (400 MHz, CDCl3): δ 8.39 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.64 - 7.57 (m, 3H), 7.32 (d, J = 8.8 Hz, 1H), 7.10 - 7.04 (m, 3H), 6.49 (d, J = 8.8 Hz, 2H), 4.88 (s, 1H), 1.18 (s, 9H). 13 13C{ 1 1H}NMR (100 MHz, CDCl3): δ 192.1, 156.2, 149.9, 147.1, 144.2, 138.8, 138.4, 137.9, 128.3, 126.3, 124.9, 122.2 (q, 1 J C-F= 289.1 Hz), 122.0, 120.9, 118.4, 115.9, 114.7, 81.3 (q, 2 J = 28.3 Hz), 34.0, 31.3. 19 19F NMR (376 MHz, CDCl3): δ -75.90 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 24 H 21 ClF3N3NaO 482.1217; Found 482.1205.

[0068] Example 4

[0069] The anti-cancer activity of the compounds provided by the present invention was evaluated by CCK-8 assay through the study of cell anti-proliferative activity.

[0070] The specific method is as follows: First, Hela, A549 or HCT-116 cells were seeded into a 96-well plate containing 100 μL of medium per well at a density of 4000 cells per well and incubated overnight at 37 °C in a 5% CO2 environment. The next day, different concentrations of the test compounds prepared in 100 μL of medium were added to each well according to the plate map. Then, the cells were incubated at 37 °C in a 5% CO2 environment for 48 hours. After the 96-well plate was equilibrated to room temperature, 10 μL of CCK-8 was added to each well and mixed on an orbital shaker for 2 minutes to induce cell lysis. After incubation at 37 °C in a 5% CO2 environment for 1.5 hours, the absorbance at 450 nm was measured using a multi-functional microplate reader (PerkinElmer), and the IC 50 value was calculated using GraphPad Prism 6.0 software. All experiments were performed in duplicate with two parallel samples. 5-Fluorouracil (5-FU) was used as a positive control drug.

[0071] The anti-cancer activity results of some compounds are as follows:

[0072]

[0073] The activity results show that the trifluoromethyl-substituted indolinone compounds 3 provided by the present invention can inhibit the proliferation activities of three cancer cells, namely Hela, A549 and HCT-116. Among them, 3z has a significant inhibitory effect on the proliferation of all three cancer cells, while compounds 3v and 3y can significantly inhibit the proliferation of HCT-116 cancer cells. These activity results suggest that this class of compounds has medicinal value for the prevention / treatment / inhibition of the progression of cancer, especially cervical cancer, lung cancer and colon cancer.

[0074] The above embodiments have described the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What is described in the above embodiments and the specification only illustrates the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. Trifluoromethyl substituted indolinone compound 3, characterized in that: The general structural formula is: Wherein: R 1 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, phenyl or halogen; R 2 is selected from hydrogen, C 1-4 alkyl or halogen; R 3 is selected from C 1-4 linear alkyl, phenyl-substituted C 1-4 linear alkyl, phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is C 1-4 alkyl, C 1-4 alkoxy or halogen.

2. The trifluoromethyl-substituted indolinone compound 3 according to claim 1, wherein: The specific structure is 3. Use of the trifluoromethyl-substituted indolinone compound 3 as claimed in claim 1 or 2 in the preparation of drugs for treating cervical cancer, lung cancer and colon cancer.

4. Use of the trifluoromethyl-substituted indolinone compound 3 according to claim 3 in the preparation of anti-cervical cancer, lung cancer and / or colon cancer drugs, wherein the anti-cervical cancer, lung cancer and colon cancer drugs are respectively used to inhibit the proliferation of three cancer cells: Hela, A549 and HCT-116.

5. A pharmaceutical composition for treating cervical cancer, colon cancer and / or lung cancer, wherein the active ingredient comprises the trifluoromethyl-substituted indolinone compound according to claim 1 or 2.

6. The synthetic method of the trifluoromethyl-substituted indolinone compound 3 as described in claim 1, wherein, The method comprises the following steps: mixing an N-phenylpyridine-2-amine compound 1, a trifluoromethylimine sulfoxide ylide compound 2, a rhodium catalyst, an additive and an organic solvent, and heating the mixture under an oxygen-containing atmosphere to react to obtain a trifluoromethyl-substituted indolinone compound 3; the reaction equation is expressed as: Where: R 1 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl or halogen; R 2 Selected from hydrogen, C 1-4 Alkyl or halogen; R 3 Selected from C 1-4 Chain alkyl, phenyl substituted C 1-4 Chain alkyl, phenyl or substituted phenyl, the substituent on the phenyl ring of substituted phenyl is C 1-4 Alkyl, C 1-4 Alkoxy or halogen.

7. The method for synthesizing the trifluoromethyl-substituted indolinone compound 3 according to claim 6, characterized in that: The rhodium catalyst is selected from [RhCp*Cl2]2; the additive is a mixture of silver hexafluoroantimonate and a copper salt, and the copper salt is copper acetate, copper acetate monohydrate, copper chloride or copper bromide.

8. The synthetic method of the trifluoromethyl-substituted indolinone compound 3 according to claim 7, wherein: The molar ratio of the compound 1, the compound 2, the rhodium catalyst, the silver hexafluoroantimonate and the copper salt is 1-1.5:1-3:0.02-0.07:0.1-1:0.1-2.

9. The synthesis method of the trifluoromethyl-substituted indolinone compound 3 according to claim 6, characterized in that: The organic solvent is selected from trifluoroethanol or a mixture of trifluoroethanol and ethanol.

10. The synthetic method of the trifluoromethyl-substituted indolinone compound 3 according to claim 6, wherein: The oxygen-containing atmosphere is selected from air or oxygen atmosphere; the reaction temperature is 30-90°C.

Images