Preparation method of 3-hydroxy-2-indolone derivative

Abstract

The invention relates to the technical field of organic synthesis, in particular to a preparation method of a 3-hydroxy-2-indolone derivative. According to the invention, commercialized cheap and easily available Ni (cod) 2 is used as a catalyst, isatin and allyl alcohol are used as raw materials, toluene is used as a solvent, other ligands do not need to be added additionally, and a series of 3-hydroxy-2-indolone derivative skeletons with novel structures are efficiently synthesized in one step. The method has the advantages of small catalyst dosage (only 1.0 mol%), cheap and easily available raw materials, simple operation, wide substrate application range, high atom economy and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly to a method for preparing 3-hydroxy-2-indolinone derivatives. Background Art

[0002] 3-Hydroxy-2-indolinone and its derivatives are a class of organic compounds that have important applications in the fields of medicine, pesticides, and chemical engineering. They possess various biological activities, including anti-cancer, antibacterial, and anti-inflammatory properties. Therefore, optimizing their preparation methods is of great significance and can promote the development and application of related products. However, the current preparation technologies face various challenges, such as complex reaction steps, low product yields, and environmentally unfriendly reaction conditions, which restrict their large-scale production and application.

[0003] Traditional methods for preparing 3-hydroxy-2-indolinone derivatives usually rely on multi-step classical organic synthesis with the construction and functionalization of heterocycles as the core. Although these methods can obtain the target products, they are accompanied by the following types of problems: (1) numerous reaction steps: multi-step reactions require frequent separation and purification processes, increasing the complexity and time cost of production. (2) harsh chemical reaction conditions: conditions such as high temperature, high pressure, or the use of strong acids and strong bases not only require high equipment requirements but also have higher energy consumption compared to conventional conditions. (3) low product yields: many side reactions occur, and the yields of target products are often unsatisfactory, and the selective synthesis of some derivatives is difficult. (4) environmentally unfriendly: the use of traditional reagents often produces a large amount of waste liquid and by-products, increasing the treatment cost and environmental burden.

[0004] In medicinal chemistry, the 3-hydroxy-2-indolinone structure plays an important role in the regulation of various enzymes and receptors and is the core skeleton of many important drugs such as tyrosine kinase inhibitors. Such compounds can inhibit cancer cell proliferation by regulating signal pathways. In addition, in materials science, their optoelectronic properties have also been widely studied, providing the possibility for the development of new materials. Such a broad application prospect makes it inevitable to develop an efficient and environmentally friendly preparation method. Summary of the Invention

[0005] The present invention provides a method for preparing 3-hydroxy-2-indolinone derivatives, comprising: mixing the compounds of formula 1 and formula 2 with the catalyst Ni(cod)2, heating and reacting in a solvent, and obtaining the 3-hydroxy-2-indolinone derivative shown in formula 3 after purifying the product;

[0006]

[0007] The molar ratio of the compounds of formula 1 and formula 2 is 1:(1 - 2).

[0008] As a preferred embodiment, the solvent includes at least one of toluene, pentane, hexane, octane, cyclohexane, cyclohexanone, benzene, and xylene.

[0009] As a preferred embodiment, the temperature of the heating reaction is 110 - 130 °C, and the reaction time is 8 - 15 h.

[0010] As a preferred embodiment, R1 is any one of phenyl, benzyl, p-methoxybenzyl, allyl, and alkyl; R2 is any one of methoxy, chloro, trifluoromethyl, and methyl; R3 is any one of methoxy and fluoro.

[0011] As a preferred embodiment, R4 is any one of methoxy, trifluoromethoxy, chloro, fluoro, and alkyl; R5 is hydrogen.

[0012] As a preferred embodiment, R6 - R10 are any one of alkyl, methoxy, trifluoromethoxy, chloro, fluoro, furan, thiophene, ferrocene substituent, allyl, and heterocycle.

[0013] As a preferred embodiment, the alkyl group has 1 - 10 carbon atoms.

[0014] As a preferred embodiment, the purification method includes: filtering the product through a short silica gel column, concentrating it in vacuo to obtain a crude product, and purifying it by column chromatography on silica gel to obtain the 3-hydroxy-2-indolinone derivative shown in Formula 3.

[0015] As a preferred embodiment, a mixed solution of ethyl acetate and n-hexane is used as the eluent for the column chromatography.

[0016] As a preferred embodiment, dichloromethane is used as the eluent for the filtration.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] The present invention uses commercially available and inexpensive Ni(cod)2 as a catalyst, indigo and allyl alcohol as raw materials, and toluene as a solvent, and can efficiently synthesize a series of novel 3-hydroxy-2-indolinone derivative skeletons in one step without the need to additionally add other ligands. It has many advantages such as less catalyst consumption (only 1.0 mol%), inexpensive and easily available raw materials, simple operation, wide substrate scope, and high atom economy. Description of the Drawings

[0019] Figure 1 1H NMR spectrum of compound 3a.

[0020] Figure 2 13C NMR spectrum of compound 3a.

[0021] Figure 3 1H NMR spectrum of compound 3b

[0022] Figure 4 13C NMR spectrum of compound 3b

[0023] Figure 5 1H NMR spectrum of compound 3c

[0024] Figure 6 13C NMR spectrum of compound 3c

[0025] Figure 7 1H NMR spectrum of compound 3d

[0026] Figure 8 13C NMR spectrum of compound 3d

[0027] Figure 9 19F NMR spectrum of compound 3d

[0028] Figure 10 1H NMR spectrum of compound 3e

[0029] Figure 11 13C NMR spectrum of compound 3e

[0030] Figure 12 1H NMR spectrum of compound 3f

[0031] Figure 13 1H NMR spectrum of compound 3f

[0032] Figure 14 19F NMR spectrum of compound 3f

[0033] Figure 15 1H NMR spectrum of compound 3g

[0034] Figure 16 13C NMR spectrum of compound 3g

[0035] Figure 17 1H NMR spectrum of compound 3h

[0036] Figure 18 13C NMR spectrum of compound 3h

[0037] Figure 19 19F NMR spectrum of compound 3h

[0038] Figure 20 1H NMR spectrum of compound 3i

[0039] Figure 21 13C NMR spectrum of compound 3i

[0040] Figure 22 1H NMR spectrum of compound 3j

[0041] Figure 23 It is the carbon spectrum of compound 3j.

[0042] Figure 24 It is the fluorine spectrum of compound 3j.

[0043] Figure 25 It is the hydrogen spectrum of compound 3k.

[0044] Figure 26 It is the carbon spectrum of compound 3k.

[0045] Figure 27 It is the hydrogen spectrum of compound 3l.

[0046] Figure 28 It is the carbon spectrum of compound 3l.

[0047] Figure 29 It is the hydrogen spectrum of compound 3m.

[0048] Figure 30 It is the carbon spectrum of compound 3m. Detailed implementation manners

[0049] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without making creative efforts fall within the protection scope of the present invention.

[0050] The reaction formula of the present invention is as follows:

[0051]

[0052] Example 1:

[0053] This example provides a preparation method of 3-hydroxy-2-indolinone derivatives. Using isatin 1a and allyl alcohol 2a as raw materials, the reaction formula and experimental steps are as follows:

[0054]

[0055] In a nitrogen-filled glove box, Ni(cod)2 (1.1 mg, 0.004 mmol, 1 mol%), isatin 1a (64.4 mg, 0.4 mmol, 1.0 equiv), dry degassed toluene (2.0 mL), and allyl alcohol 2a (71.1 mg, 0.48 mmol, 1.2 equiv) were successively added to a 15 mL dry reaction tube. After sealing the reaction tube, it was taken out of the glove box. Then, the mixture was placed in a preheated heating mantle and heated at 120 °C for 10 h. Subsequently, it was cooled to room temperature and filtered through a short silica gel column (using dichloromethane as the eluent), and then concentrated in vacuo to obtain the crude product. Finally, it was purified by column chromatography on silica gel (using ethyl acetate / n-hexane as the eluent (v / v = 1:5)) to obtain the pure product 3a. It was a yellow solid with a yield of 98%.

[0056] The characterization data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.85–7.79 (m, 2H), 7.41 (dd, J = 7.4, 0.7 Hz, 1H), 7.33 (td, J = 7.8, 1.2 Hz, 1H), 7.25–7.20 (m, 2H), 7.10 (td, J = 7.6, 0.9 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 3.60 (s, 1H), 3.29–3.21 (m, 1H), 3.20 (s, 3H), 3.15–3.05 (m, 1H), 2.40 (s, 3H), 2.38–2.30 (m, 2H).

[0057] 13 13C NMR (100 MHz, CDCl3) δ 199.7, 178.0, 144.3, 143.2, 134.2, 130.6, 129.9, 129.4, 128.4, 123.9, 123.4, 108.7, 75.6, 32.8, 32.3, 26.4, 21.8.

[0058] HRMS (ESI) m / z: [M+H] + Calcd. for C 19 H 20 NO3 310.1438; Found 310.1437.

[0059] Example 2:

[0060] This example provides a method for preparing a 3-hydroxy-2-indolinone derivative. Using isatin 1b and allyl alcohol 2a as raw materials, the reaction formula and experimental procedures are as follows:

[0061]

[0062] In a nitrogen-filled glove box, Ni(cod)2 (1.1 mg, 0.004 mmol, 1 mol %), isatin 1b (76.4 mg, 0.4 mmol, 1.0 equiv), dry degassed toluene (2.0 mL), and allyl alcohol 2a (71.1 mg, 0.48 mmol, 1.2 equiv) were successively added to a 15 mL dry reaction tube. After sealing the reaction tube, it was taken out of the glove box. Then, the mixture was placed in a preheated heating mantle and heated at 120 °C for 10 h. Subsequently, it was cooled to room temperature and filtered through a short silica gel column (using dichloromethane as the eluent), and then concentrated in vacuo to obtain the crude product. Finally, it was purified by column chromatography on silica gel (using ethyl acetate / n-hexane as the eluent (v / v = 1:5)) to obtain the pure product 3b. The product was a yellow solid with a yield of 49%.

[0063] The characterization data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.07–7.00 (m, 2H), 6.94–6.85 (m, J = 6.1, 2.8 Hz, 1H), 3.85 (s, 3H), 3.47–3.45 (m, 4H), 3.24–3.14 (m, 1H), 3.08–2.96 (m, 1H), 2.38 (s, J = 10.1 Hz, 3H), 2.36–2.24 (m, 2H).

[0064] 13 13C NMR (150 MHz, CDCl3) δ 199.6, 178.2, 145.7, 144.1, 134.3, 132.3, 130.9, 129.4, 128.4, 124.0, 116.5, 113.8, 75.6, 56.2, 33.1, 32.3, 29.7, 21.8.

[0065] HRMS (ESI) m / z: [M+H] + Calcd. for C 20 H 22 NO4 340.1543; Found 340.1519.

[0066] Example 3:

[0067] This example provides a method for preparing a 3-hydroxy-2-indolinone derivative, using isatin 1c and allyl alcohol 2a as raw materials. The reaction formula and experimental procedures are as follows:

[0068]

[0069] In a nitrogen-filled glove box, Ni(cod)2 (1.1 mg, 0.004 mmol, 1 mol%), isatin 1c (78.0 mg, 0.4 mmol, 1.0 equiv), dry degassed toluene (2.0 mL), and allyl alcohol 2a (71.1 mg, 0.48 mmol, 1.2 equiv) were successively added to a 15 mL dry reaction tube. After sealing the reaction tube, it was taken out of the glove box. Then, the mixture was placed in a preheated heating mantle and heated at 120 °C for 10 h. Subsequently, it was cooled to room temperature and filtered through a short silica gel column (using dichloromethane as the eluent), and then concentrated in vacuo to obtain the crude product. Finally, it was purified by column chromatography on silica gel (using ethyl acetate / n-hexane as the eluent (v / v = 1:5)) to obtain the pure product 3c. The product was a yellow solid with a yield of 70%.

[0070] The characterization data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.86–7.78 (m, 2H), 7.34–

[0071] 7.27 (m, 1H), 7.26–7.22 (m, 3H), 7.05–6.98 (m, 1H), 3.86 (s, 1H), 3.57 (s, 3H), 3.31–3.20 (m, 1H), 3.14–3.02 (m, 1H), 2.44–2.34 (m, 4H), 2.30–2.20 (m, 1H).

[0072] 13 13C NMR (150 MHz, CDCl3) δ 199.6, 178.4, 144.3, 138.9, 134.1, 133.8, 132.0, 129.4, 128.4, 124.2, 122.5, 116.1, 75.1, 33.1, 32.1, 29.7, 21.8.

[0073] HRMS (ESI) m / z: [M+H] + Calcd. for C 19 H 19 ClNO3 344.1048; Found 344.1054.

[0074] Example 4:

[0075] This example provides a method for preparing a 3-hydroxy-2-indolinone derivative. Using isatin 1d and allyl alcohol 2a as raw materials, the reaction formula and experimental procedures are as follows:

[0076]

[0077] In a nitrogen-filled glove box, Ni(cod)2 (1.1 mg, 0.004 mmol, 1 mol%), isatin 1d (91.6 mg, 0.4 mmol, 1.0 equiv), dry degassed toluene (2.0 mL), and allyl alcohol 2a (71.1 mg, 0.48 mmol, 1.2 equiv) were successively added to a 15 mL dry reaction tube. After sealing the reaction tube, it was taken out of the glove box. Then, the mixture was placed in a preheated heating mantle and heated at 120 °C for 10 h. Subsequently, it was cooled to room temperature and filtered through a short silica gel column (using dichloromethane as the eluent), and then concentrated in vacuo to obtain the crude product. Finally, it was purified by column chromatography on silica gel (using ethyl acetate / n-hexane as the eluent (v / v = 1:5)) to obtain the pure product 3d. It was a white solid with a yield of 63%.

[0078] The characterization data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.85–7.78 (m, 2H), 7.62–

[0079] 7.56 (m, 2H), 7.25–7.20 (m, 2H), 7.20–7.13 (m, 1H), 4.15 (s, 1H), 3.39 (q, J = 2.4 Hz, 3H), 3.34–3.22 (m, 1H), 3.18–3.03 (m, 1H), 2.47–2.37 (m, 4H), 2.30–2.20 (m, 1H).

[0080] 13 13C NMR (150 MHz, CDCl3) δ 199.7, 178.9, 144.4, 141.0, 134.1, 133.7, 129.4, 128.4, 127.6 (q, J = 5.7 Hz), 127.4, 123.5 (q, J = 269.9 Hz), 122.7, 113.1 (q, J = 33.0 Hz), 73.7, 33.1, 32.0, 29.0 (q, J = 6.3 Hz), 21.8.

[0081] 19 19F NMR (376 MHz, CDCl3) δ -53.3.

[0082] HRMS (ESI) m / z: [M+H] + Calcd. for C 20 H 19 F3NO3 378.1312; Found 378.1302.

[0083] Example 5:

[0084] This example provides a method for preparing 3-hydroxy-2-indolinone derivatives. Using isatin 1e and allyl alcohol 2a as raw materials, the reaction formula and experimental steps are as follows:

[0085]

[0086] In a glove box filled with nitrogen, Ni(cod)2 (1.1 mg, 0.004 mmol, 1 mol%), isatin 1e (76.4 mg, 0.4 mmol, 1.0 equiv), dry degassed toluene (2.0 mL), and allyl alcohol 2a (71.1 mg, 0.48 mmol, 1.2 equiv) were successively added to a 15 mL dry reaction tube. After sealing the reaction tube, it was taken out of the glove box. Then, the mixture was placed in a preheated heating mantle and heated at 120 °C for 10 h. Subsequently, it was cooled to room temperature and filtered through a short silica gel column (using dichloromethane as the eluent), and then concentrated in vacuo to obtain the crude product. Finally, it was purified by column chromatography on silica gel (using ethyl acetate / n-hexane as the eluent (v / v = 1:5)) to obtain the pure product 3e. The product was a yellow solid with a yield of 74%.

[0087] The characterization data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.85–7.73 (m, 2H), 7.30 (d, J = 8.2 Hz, 1H), 7.25–7.19 (m, 2H), 6.57 (dd, J = 8.2, 2.2 Hz, 1H), 6.41 (d, J = 2.2 Hz, 1H), 3.82 (s, 3H), 3.39 (s, 1H), 3.23–3.11 (m, 4H), 3.10–2.99 (m, 1H), 2.40 (s, 3H), 2.36–2.29 (m, 2H).

[0088] 13 13C NMR (100 MHz, CDCl3) δ 199.5, 178.5, 161.4, 144.6, 144.1, 134.2, 129.3, 128.4, 124.8, 122.4, 106.7, 96.8, 75.4, 55.7, 32.9, 32.4, 26.3, 21.7.

[0089] HRMS (ESI) m / z: [M+H] + Calcd. for C 20 H 22 NO4 340.1543; Found 340.1569.

[0090] Example 6:

[0091] This example provides a method for preparing 3-hydroxy-2-indolinone derivatives. Using isatin 1f and allyl alcohol 2a as raw materials, the reaction formula and experimental steps are as follows:

[0092]

[0093] In a glove box filled with nitrogen, Ni(cod)2 (1.1 mg, 0.004 mmol, 1 mol%), isatin 1f (71.6 mg, 0.4 mmol, 1.0 equiv), dry degassed toluene (2.0 mL), and allyl alcohol 2a (71.1 mg, 0.48 mmol, 1.2 equiv) were successively added to a 15 mL dry reaction tube. After sealing the reaction tube, it was taken out of the glove box. Then, the mixture was placed in a preheated heating mantle and heated at 120 °C for 10 h. Subsequently, it was cooled to room temperature and filtered through a short silica gel column (using dichloromethane as the eluent), and then concentrated in vacuo to obtain the crude product. Finally, it was purified by column chromatography on silica gel (using ethyl acetate / n-hexane as the eluent (v / v = 1:5)) to obtain the pure product 3f. The product was a yellow solid with a yield of 47%.

[0094] The characterization data are as follows: 1 HNMR(400MHz,CDCl3)δ7.85–7.78(m,2H),7.35(dd,J=8.2,5.3Hz,1H),7.26–7.21(m,2H),6.80–6.73(m,1H),6.57(dd,J=8.8,2.3Hz,1H),3.69(s,1H),3.28–3.20(m,1H),3.18(s,3H),3.14–3.06(m,1H),2.41(s,3H),2.37–2.28(m,2H).

[0095] 13 C NMR(150MHz,CDCl3)δ199.6,178.3,166.4(d,J=247.0Hz),144.9(d,J=11.6Hz),144.3,134.2,129.4,128.4,126.1(d,J=3.0Hz),125.2(d,J=9.8Hz),109.2(d,J=22.3Hz),97.6(d,J=27.6Hz),75.3,32.8,32.2,26.5,21.8.

[0096] 19 F NMR(376MHz,CDCl3)δ-109.7.

[0097] HRMS(ESI) m / z: [M+H] + Calcd. for C 19 H 19 FNO3 328.1343; Found 328.1367.

[0098] Example 7:

[0099] This example provides a method for preparing a 3-hydroxy-2-indolinone derivative. Using isatin 1 g and allyl alcohol 2a as raw materials, the reaction formula and experimental steps are as follows:

[0100]

[0101] In a glove box filled with nitrogen, Ni(cod)2 (1.1 mg, 0.004 mmol, 1 mol%), isatin 1 g (76.4 mg, 0.4 mmol, 1.0 equiv), dry degassed toluene (2.0 mL), and allyl alcohol 2a (71.1 mg, 0.48 mmol, 1.2 equiv) were successively added to a 15 mL dry reaction tube. After sealing the reaction tube, it was taken out of the glove box. Then, the mixture was placed in a preheated heating mantle and heated at 120 °C for 10 h. Subsequently, it was cooled to room temperature and filtered through a short silica gel column (using dichloromethane as the eluent), and then concentrated in vacuo to obtain the crude product. Finally, it was purified by column chromatography on silica gel (using ethyl acetate / n-hexane as the eluent (v / v = 1:5)) to obtain 3 g of the pure product. The property is a yellow solid, and the yield is 61%.

[0102] The characterization data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.86–7.71 (m, 2H), 7.25–

[0103] 7.18 (m, 2H), 7.03 (s, 1H), 6.88–6.80 (m, 1H), 6.79–6.69 (m, 1H), 3.79 (s, 3H), 3.61 (s, 1H), 3.29–3.19 (m, 1H), 3.18 (s, 3H), 3.13–2.98 (m, 1H), 2.40 (s, 3H), 2.37–2.23 (m, 2H).

[0104] 1313C NMR (100 MHz, CDCl3) δ 199.6, 177.8, 156.6, 144.1, 136.4, 134.2, 131.9, 129.3, 128.4, 114.4, 111.0, 109.1, 76.0, 56.0, 32.9, 32.3, 26.4, 21.7.

[0105] HRMS (ESI) m / z: [M+H] + Calcd. for C 20 H 22 NO4340.1543; Found 340.1562.

[0106] Example 8:

[0107] This example provides a method for preparing a 3-hydroxy-2-indolinone derivative. Using isatin 1h and allyl alcohol 2a as raw materials, the reaction formula and experimental procedures are as follows:

[0108]

[0109] In a glove box filled with nitrogen, Ni(cod)2 (1.1 mg, 0.004 mmol, 1 mol%), isatin 1h (98.0 mg, 0.4 mmol, 1.0 equiv), dry degassed toluene (2.0 mL), and allyl alcohol 2a (71.1 mg, 0.48 mmol, 1.2 equiv) were successively added to a 15 mL dry reaction tube. After sealing the reaction tube, it was taken out of the glove box. Then, the mixture was placed in a preheated heating mantle and heated at 120 °C for 10 h. Subsequently, it was cooled to room temperature and filtered through a short silica gel column (using dichloromethane as the eluent), and then concentrated in vacuo to obtain the crude product. Finally, it was purified by column chromatography on silica gel (using ethyl acetate / n-hexane as the eluent (v / v = 1:5)) to obtain the pure product 3h. The product was a yellow solid with a yield of 75%.

[0110] The characterization data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.90–7.81 (m, 2H), 7.35–

[0111] 7.31 (m, 1H), 7.29–7.25 (m, 2H), 7.23 (dd, J = 8.5, 1.4 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 4.12 (s, 1H), 3.40–3.29 (m, 1H), 3.27–3.15 (m, 4H), 2.43 (s, 3H), 2.41–2.35 (m, 1H), 2.35–2.22 (m, 1H).

[0112] 13 13C NMR(150MHz,CDCl3)δ199.7,178.0,145.3,144.4,141.7,134.1,132.5,129.4,128.4,122.8,120.6(q,J=257.2Hz),118.0,109.2,75.6,32.8,32.1,26.5,21.8.

[0113] 19 19F NMR(376MHz,CDCl3)δ -58.3.

[0114] HRMS(ESI)m / z:[M+H] + Calcd.for C 20 H 19 F3NO4394.1261;Found 394.1280.

[0115] Example 9:

[0116] This example provides a method for preparing a 3-hydroxy-2-indolinone derivative, using isatin 1i and allyl alcohol 2a as raw materials. The reaction formula and experimental procedure are as follows:

[0117]

[0118] In a glove box filled with nitrogen, Ni(cod)2(1.1mg, 0.004mmol, 1mol%), isatin 1i(78.0mg, 0.4mmol, 1.0equiv), dry degassed toluene(2.0mL), and allyl alcohol 2a(71.1mg, 0.48mmol, 1.2equiv) were successively added to a 15mL dry reaction tube. After sealing the reaction tube, it was taken out of the glove box. Then, the mixture was placed in a preheated heating mantle and heated at 120°C for 10h. Subsequently, it was cooled to room temperature and filtered through a short silica gel column (using dichloromethane as the eluent), and then concentrated in vacuo to obtain the crude product. Finally, it was purified by column chromatography on silica gel (using ethyl acetate / n-hexane as the eluent (v / v = 1:5)) to obtain the pure product 3i. The product is a light red solid with a yield of 81%.

[0119] The characterization data are as follows: 1 1H NMR(400MHz,CDCl3)δ7.87–7.79(m,2H),7.41–

[0120] 7.35 (m, 1H), 7.30 (dd, J = 8.3, 2.0 Hz, 1H), 7.26–7.21 (m, 2H), 6.76 (d, J = 8.3 Hz, 1H), 4.05 (s, 1H), 3.34–3.22 (m, 1H), 3.22–3.05 (m, 4H), 2.41 (s, 3H), 2.39–2.31 (m, 1H), 2.31–2.20 (m, 1H).

[0121] 13 C NMR (150 MHz, CDCl3) δ 199.7, 177.7, 144.3, 141.6, 134.1, 132.6, 129.6, 129.4, 128.8, 128.4, 125.4, 124.5, 109.6, 75.6, 32.8, 32.2, 26.5, 21.8.

[0122] HRMS (ESI) m / z: [M + H] + Calcd. for C 19 H 19 ClNO3 344.1048; Found 344.1020.

[0123] Example 10:

[0124] This example provides a method for preparing a 3-hydroxy-2-indolinone derivative, using isatin 1j and allyl alcohol 2a as raw materials. The reaction formula and experimental procedure are as follows:

[0125]

[0126] In a nitrogen-filled glove box, Ni(cod)2 (1.1 mg, 0.004 mmol, 1 mol%), isatin 1j (71.6 mg, 0.4 mmol, 1.0 equiv), dry degassed toluene (2.0 mL), and allyl alcohol 2a (71.1 mg, 0.48 mmol, 1.2 equiv) were successively added to a 15 mL dry reaction tube. After sealing the reaction tube, it was taken out of the glove box. Then, the mixture was placed in a preheated heating mantle and heated at 120 °C for 10 h. Subsequently, it was cooled to room temperature and filtered through a short silica gel column (using dichloromethane as the eluent), and then concentrated in vacuo to obtain the crude product. Finally, it was purified by column chromatography on silica gel (using ethyl acetate / n-hexane as the eluent (v / v = 1:5)) to obtain the pure product 3j. The product was a yellow oil with a yield of 70%.

[0127] The characterization data are as follows: 11H NMR (600 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.16 (dd, J = 7.5, 2.4 Hz, 1H), 7.01 (td, J = 8.8, 2.5 Hz, 1H), 6.75 (dd, J = 8.5, 3.9 Hz, 1H), 4.16 (s, 1H), 3.27–3.20 (m, 1H), 3.17 (s, 3H), 3.14–3.07 (m, 1H), 2.39 (s, 3H), 2.38–2.32 (m, 1H), 2.31–2.24 (m, 1H).

[0128] 13 13C NMR (150 MHz, CDCl3) δ 199.6, 178.0, 159.6 (d, J = 242.5 Hz), 144.3, 138.9, 134.2, 132.5 (d, J = 7.6 Hz), 129.4, 128.4, 115.9 (d, J = 23.4 Hz), 112.2 (d, J = 25.1 Hz), 109.2 (d, J = 8.2 Hz), 75.8, 32.8, 32.1, 26.5, 21.7.

[0129] 19 19F NMR (376 MHz, CDCl3) δ -119.5.

[0130] HRMS (ESI) m / z: [M+H] + Calcd. for C 19 H 19 FNO3 328.1343; Found 328.1340.

[0131] Example 11:

[0132] This example provides a method for preparing a 3-hydroxy-2-indolinone derivative, using isatin 1k and allyl alcohol 2a as raw materials. The reaction formula and experimental procedures are as follows:

[0133]

[0134] In a nitrogen-filled glove box, Ni(cod)2 (1.1 mg, 0.004 mmol, 1 mol%), isatin 1k (75.6 mg, 0.4 mmol, 1.0 equiv), dry degassed toluene (2.0 mL), and allyl alcohol 2a (71.1 mg, 0.48 mmol, 1.2 equiv) were successively added to a 15 mL dry reaction tube. After sealing the reaction tube, it was taken out of the glove box. Then, the mixture was placed in a preheated heating mantle and heated at 120 °C for 10 h. Subsequently, it was cooled to room temperature and filtered through a short silica gel column (using dichloromethane as the eluent), and then concentrated in vacuo to obtain the crude product. Finally, it was purified by column chromatography on silica gel (using ethyl acetate / n-hexane as the eluent (v / v = 1:5)) to obtain the pure product 3k. It was a pale red solid with a yield of 68%.

[0135] The characterization data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.92–7.86 (m, 2H), 7.33–

[0136] 7.29 (m, 2H), 7.14 (s, 1H), 6.93 (s, 1H), 3.54–3.49 (m, 4H), 3.31–3.19 (m, 1H), 3.16–3.04 (m, 1H), 2.58 (s, 3H), 2.48 (s, 3H), 2.47–2.40 (m, 1H), 2.36 (s, 3H), 2.35–2.28 (m, 1H).

[0137] 13 13C NMR (100 MHz, CDCl3) δ 199.6, 178.7, 144.0, 138.3, 134.3, 133.9, 132.9, 131.4, 129.3, 128.4, 122.5, 120.0, 75.1, 33.2, 32.4, 29.7, 21.7, 20.9, 18.9.

[0138] HRMS (ESI) m / z: [M+H] + Calcd. for C 21 H 24 NO3 338.1751; Found 338.1758.

[0139] Example 12:

[0140] This example provides a method for preparing a 3-hydroxy-2-indolinone derivative, using isatin 1l and allyl alcohol 2a as raw materials. The reaction formula and experimental procedures are as follows:

[0141]

[0142] In a nitrogen-filled glove box, Ni(cod)2 (1.1 mg, 0.004 mmol, 1 mol%), isatin 1l (89.2 mg, 0.4 mmol, 1.0 equiv), dry degassed toluene (2.0 mL), and allyl alcohol 2a (71.1 mg, 0.48 mmol, 1.2 equiv) were successively added to a 15 mL dry reaction tube. After sealing the reaction tube, it was taken out of the glove box. Then, the mixture was placed in a preheated heating mantle and heated at 120 °C for 10 h. Subsequently, it was cooled to room temperature and filtered through a short silica gel column (using dichloromethane as the eluent), and then concentrated in vacuo to obtain the crude product. Finally, it was purified by column chromatography on silica gel (using ethyl acetate / n-hexane as the eluent (v / v = 1:5)) to obtain the pure product 3l. The product was a yellow solid with a yield of 62%.

[0143] The characterization data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.88–7.78 (m, 2H), 7.56–

[0144] 7.47 (m, 3H), 7.45–7.39 (m, 3H), 7.28–7.23 (m, 3H), 7.14 (td, J = 7.6, 0.8 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 3.71 (s, 1H), 3.41–3.26 (m, 1H), 3.25–3.12 (m, 1H), 2.56–2.41 (m, 2H), 2.40 (s, 3H).

[0145] 13 13C NMR (150 MHz, CDCl3) δ 199.6, 177.4, 144.3, 143.2, 134.3, 134.2, 130.4, 129.8, 129.8, 129.4, 128.4, 128.4, 126.5, 124.3, 123.8, 110.0, 75.8, 33.4, 32.4, 21.8.

[0146] HRMS (ESI) m / z: [M+H] + Calcd. for C 24 H 22 NO3 372.1594; Found 372.1597.

[0147] Example 13:

[0148] This example provides a method for preparing 3-hydroxy-2-indolinone derivatives, using isatin 1m and allyl alcohol 2a as raw materials. The reaction formula and experimental steps are as follows:

[0149]

[0150] In a glove box filled with nitrogen, Ni(cod)2 (1.1 mg, 0.004 mmol, 1 mol%), isatin 1m (74.8 mg, 0.4 mmol, 1.0 equiv), dry degassed toluene (2.0 mL), and allyl alcohol 2a (71.1 mg, 0.48 mmol, 1.2 equiv) were successively added to a 15 mL dry reaction tube. After sealing the reaction tube, it was taken out of the glove box. Then, the mixture was placed in a preheated heating jacket and heated at 120 °C for 10 h. Subsequently, it was cooled to room temperature and filtered through a short silica gel column (using dichloromethane as the eluent), and then concentrated in vacuo to obtain the crude product. Finally, it was purified by column chromatography on silica gel (using ethyl acetate / n-hexane as the eluent (v / v = 1:5)) to obtain the pure product 3m. The product was a white solid with a yield of 76%.

[0151] The characterization data are as follows: 1 HNMR(400MHz,CDCl3)δ7.85–7.77(m,2H),7.42(d,J=7.3Hz,1H),7.29(td,J=7.8,1.0Hz,1H),7.25–7.20(m,2H),7.12–7.06(m,1H),6.84(d,J=7.8Hz,1H),5.92–5.75(m,1H),5.28–5.20(m,2H),4.46–4.37(m,1H),4.26–4.17(m,1H),3.70(s,1H),3.29–3.16(m,1H),3.16–3.00(m,1H),2.42–2.33(m,5H).

[0152] 13 C NMR(150MHz,CDCl3)δ199.5,177.8,144.1,142.3,134.2,131.3,130.6,129.7,129.4,128.4,124.0,123.3,117.9,109.5,75.7,42.4,33.0,32.4,21.7.

[0153] HRMS(ESI)m / z:[M+H] + Calcd.for C 21 H 22NO3336.1594; Found 336.1614.

[0154] The above are the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing a 3-hydroxy-2-indolinone derivative, characterized in that, Comprising: Mix the compounds of Formula 1 and Formula 2 with the catalyst Ni(cod)2, heat and react in a solvent, and after purification of the product, obtain the 3-hydroxy-2-indolinone derivative shown in Formula 3; The molar ratio of the compounds of Formula 1 and Formula 2 is 1:(1 - 2).

2. The preparation method according to claim 1, characterized in that, The solvent includes at least one of toluene, pentane, hexane, octane, cyclohexane, cyclohexanone, benzene, and xylene.

3. The preparation method according to claim 1, characterized in that, The temperature of the heating reaction is 110 - 130 °C, and the reaction time is 8 - 15 h.

4. The preparation method according to claim 1, wherein, The R 1 is any one of phenyl, benzyl, p-methoxybenzyl, allyl, and alkyl; R 2 is any one of methoxy, chlorine, trifluoromethyl, and methyl; R 3 is any one of methoxy and fluorine.

5. The preparation method according to claim 1, characterized in that, R 4 is any one of methoxy, trifluoromethoxy, chlorine, fluorine, and alkyl; R 5 is hydrogen.

6. The preparation method according to claim 1, characterized in that, The R 6 to R 10 is any one of an alkyl group, a methoxy group, a trifluoromethoxy group, chlorine, fluorine, furan, thiophene, a ferrocene substituent, an allyl group, and a heterocycle.

7. The preparation method according to claim 6, characterized in that, The number of carbon atoms of the alkyl group is 1 - 10.

8. The preparation method according to claim 1, characterized in that, The purification method includes: filtering the product through a short silica gel column, concentrating in vacuo to obtain a crude product, and purifying by column chromatography on silica gel to obtain the 3-hydroxy-2-indolinone derivative shown in Formula 3.

9. The preparation method according to claim 8, characterized in that, The column chromatography uses a mixed solution of ethyl acetate and n-hexane as the eluent.

10. The preparation method according to claim 8, wherein The filtration uses dichloromethane as the eluent.

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