A process for the preparation of a 3-hydroxy-2-indolone compound

Abstract

The application discloses a preparation method of 3-hydroxy-2-indolone compounds. An o-iodo aryl alpha-ketoamide is reacted with sodium hydride in a solvent, the sodium hydride is activated and Na-I exchange reaction with iodobenzene occurs, and then intramolecular nucleophilic attack on the ketone carbonyl of the alpha-ketoamide is carried out, so that a series of 3-hydroxy-2-indolone derivatives which are difficult to synthesize by other methods are prepared. The method is simple in operation and mild in reaction condition, and does not need any transition metal catalyst, so that the method provides a new, direct and efficient synthesis strategy for preparing 3-hydroxy-2-indolone compounds. The method for preparing 3-hydroxy-2-indolone products has application value in drug synthesis.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing 3-hydroxy-2-indolone from o-iodoaryl α-ketoamides via intramolecular cyclization. Background Technology

[0002] 3-Hydroxy-2-indolinones are the core structure of many drugs and natural products, exhibiting a wide range of biological activities. Representative compounds include Convolutamydine A, Maremycin B, donaxaridine, 3-hydroxywelwit-indolinones, TMC-95A, and SM-130686.

[0003]

[0004] In addition, 3-hydroxy-2-indolone is also an important intermediate in organic synthesis. For example, 3-hydroxy-2-indolone can be used to efficiently synthesize 3,3-disubstituted-2-indolone by in-situ activation of 3-hydroxy-2-indolone in the form of trichloroacetonitrile via an acid-catalyzed substitution reaction.

[0005]

[0006] For example, 3,3-disubstituted-2-indolone can be synthesized by reacting 3-hydroxy-2-indolone with various aromatic and heteroaromatic hydrocarbons via a Friedel-Craft reaction catalyzed by Hg(ClO4)2·3H2O.

[0007]

[0008] Existing synthetic methods for 3-hydroxy-2-indolone include: reacting indigo with Grignard reagents, lithium reagents, etc.; or using α-ketoaniline as a starting material, and activating the intramolecular aryl trifluoro ester (or other halogen) with palladium catalysis in the presence of phosphate, ligands, and triethylamine to achieve the addition cyclization of the intramolecular ketone group. However, palladium catalysts are expensive, and the reaction temperature and reaction time are high, reducing the practical value of these methods.

[0009]

[0010] In summary, existing methods for synthesizing 3-hydroxy-2-indolones either require highly reactive reagents and harsh reaction conditions, or rely on expensive metal catalysis, resulting in high costs and the risk of heavy metal residues in the products. Therefore, there is a need to develop a new method that can prepare 3-hydroxy-2-indolone compounds from simple raw materials using inexpensive initiating reagents under milder conditions. Summary of the Invention

[0011] This invention discloses a method for synthesizing 3-hydroxy-2-indolone compounds from o-iodoaryl α-ketoamides, using a commercially available 60% NaH mineral oil dispersion as the initiator. The method is simple to operate, operates under mild conditions, does not require transition metal catalysis or strictly anhydrous conditions, and is easy to scale up. This method employs a novel approach, activating the nucleophilic activity of NaH to initiate Na-I exchange and intramolecularly attack the ketone carbonyl group, ultimately yielding the cyclized product 3-hydroxy-2-indolone. This invention solves the problems of harsh conditions, high reagent costs, and heavy metal residues associated with traditional methods for preparing such products.

[0012] The present invention adopts the following technical solution:

[0013] A method for preparing a 3-hydroxy-2-indolone compound includes the following steps: reacting an o-iodoaryl α-ketoamide in a solvent in the presence of sodium hydride to obtain the 3-hydroxy-2-indolone compound.

[0014] In this invention, the molar ratio of o-iodoaryl α-ketoamide and sodium hydride is 1:(2-5), preferably 1:3.

[0015] In this invention, the reaction temperature is 40–120°C and the reaction time is 2–48 hours; preferably, the reaction temperature is 80–100°C and the reaction time is 10–15 hours.

[0016] In this invention, the solvent is tetrahydrofuran or 1,4-dioxane, preferably 1,4-dioxane.

[0017] In this invention, the chemical structural formula of the o-iodoaryl α-ketoamide is as follows:

[0018]

[0019] The chemical structural formula of the product, 3-hydroxy-2-indolone, is as follows:

[0020]

[0021] Where Ar is a benzene ring or heterocycle, such as a pyridine ring; R is a substituted phenyl or aromatic heterocycle, tert-butyl, cyclopropyl, etc.; R 1 Halogen, tert-butyl, methoxy, trifluoromethyl, etc.; R 2 It includes various straight-chain alkanes, branched-chain alkanes, and cycloalkanes, such as methyl, ethyl, propyl, isobutyl, n-pentyl, cyclobutyl, and cyclopentyl.

[0022] Existing technologies use ortho-halo (or OTf) aryl α-ketoamides as raw materials, utilizing transition metal catalysis to preferentially attack the ketone carbonyl group, followed by an intramolecular reaction to synthesize 3-hydroxy-2-indolone compounds. However, these catalysts are expensive and the reaction conditions are demanding. This invention discloses for the first time a novel approach using sodium hydride as an activator, employing a Na-I exchange reaction and intramolecular addition to the ketone carbonyl group to obtain 3-hydroxy-2-indolone compounds. The method of this invention is carried out under relatively mild reaction conditions, is simple to operate, and does not require any transition metal catalysis or strictly anhydrous conditions. Such transformations are difficult to achieve using traditional methods such as Grignard reagents, alkyllithium, and aminolithium. Therefore, this invention provides a novel method that enables the preparation of 3-hydroxy-2-indolone compounds from simple raw materials using inexpensive initiating reagents under relatively mild conditions. Detailed Implementation

[0023] This invention uses o-iodoaryl α-ketoamides as raw materials and reacts them in a solvent in the presence of sodium hydride, a basic metal hydride, to obtain 3-hydroxy-2-indolone compounds without the need for Grignard reagents, metals, or metal compound catalysts. Specifically, NaH is weighed into a sealed tube, anhydrous 1,4-dioxane is added, and under stirring, a solution of o-iodoaryl α-ketoamides in 1,4-dioxane is added. Nitrogen gas is introduced into the sealed tube, and the reaction is carried out at 90 °C for 12 h to obtain 3-hydroxy-2-indolone derivatives.

[0024] To provide a clearer understanding of the technical content of this invention, the following embodiments are provided for detailed description. All raw materials are commercially available products or prepared according to literature methods, and the specific operations and testing methods are conventional techniques.

[0025] NMR spectrum 1 H NMR and 13 All C NMR measurements were performed using an Agilent 400 MHz and a Bruker 400 MHz instrument. The sample solvent was CDCl3 (7.26 ppm). NMR data reports include: chemical shift, peak area integral, coupling constant, peak shape, etc. TLC plates were manufactured by Yantai Huanghai Chemical Plant, and visualization was performed at wavelengths of 254 nm and 365 nm. The silica gel used for rapid column chromatography was 200-300 mesh. All reagents used were commercially available analytical grade or chemically pure, and were used directly unless otherwise specified. Anhydrous solvents were all redistilled solvents or commercially available dried solvents (such as Bailingwei). Example 1

[0026] Weigh NaH (60% in oil) into a sealed tube, add anhydrous 1,4-dioxane, stir at room temperature for 5 min, add o-iodoaryl α-ketoamide 1a, fill the sealed tube with N2, and then place the reactants at 90℃ for 12 hours. Then, quench the reaction with saturated NH4Cl solution under ice bath conditions, extract the aqueous phase three times with ethyl acetate, combine the organic phases, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter, vacuum dry, and then purify and separate by silica gel column chromatography to obtain the corresponding product 2a, with a yield of 48%.

[0027] The reaction results under different operating conditions are shown in Table 1.

[0028] Table 1 Results under different reaction conditions

[0029]

[0030] Example 2

[0031] Weigh 36 mg of NaH (60% in oil, 0.9 mmol, 3.0 equiv) into a 10 mL sealed tube, add 1 mL of anhydrous 1,4-dioxane, and stir at room temperature for 5 min. Then add o-iodoaryl α-ketoamides 1b-1e (0.3 mmol, 1.0 equiv, dissolved in 1 mL of 1,4-dioxane) sequentially, purge the sealed tube with N2, and react at 90 ℃ for 12 h. Then quench the reaction with saturated NH4Cl solution under ice bath conditions. Transfer the reaction solution to a separatory funnel, extract the aqueous phase three times with ethyl acetate, and finally combine the organic phases, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter, vacuum dry, and then purify and separate by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the corresponding products (2b-2e).

[0032] The different reaction substrates (o-iodoaryl α-ketoamides 1a-1e) and the resulting 3-hydroxy-2-indole ketone derivatives 2a-2e are shown in Table 2.

[0033] Table 2. Reactions of o-iodoaryl α-ketoamides 1a-1e

[0034]

[0035] The above product data are characterized as follows:

[0036] 3-hydroxy-1-methyl-3-phenylindolin-2-one (2a): 1H NMR (400 MHz,CDCl3): δ 7.40 – 7.36 (m, 2H), 7.33 (ddd, J = 6.2, 4.4, 1.4 Hz, 2H), 7.31 –7.25 (m, 3H), 7.08 (t, J = 8 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 3.44 (s, 1H),3.24 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 177.58 (s), 143.52 (s), 140.12 (s),131.60 (s), 129.90 (s), 128.61 (s), 128.32 (s), 125.36 (s), 124.96 (s),123.58 (s), 108.72 (s), 78.00 (s), 26.55 (s). HRMS (ESI): calculated for[C 15 H 14 NO2 (M+H)] + : 240.1019, found: 240.1018.

[0037] 3-hydroxy-1-methyl-3-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (2b) : 1 H NMR (400 MHz, CDCl3): δ 8.17 (dd, J = 5.3, 1.5 Hz, 1H), 7.50 (dd, J = 7.3, 1.5 Hz, 1H), 7.39 – 7.34 (m, 2H), 7.33 – 7.29 (m, 3H), 6.95 (dd, J =7.3, 5.3 Hz, 1H), 4.57 (s, 1H), 3.27 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ177.56 (s), 156.91 (s), 148.40 (s), 139.23 (s), 132.49 (s), 128.75 (s),128.62(s), 126.51 (s), 125.33 (s), 119.04 (s), 77.66 (s), 25.62 (s).

[0038] 5-chloro-3-hydroxy-1-methyl-3-phenylindolin-2-one (2c): 1 H NMR (400MHz, CDCl3): δ 7.35 – 7.27 (m, 6H), 7.23 (d, J = 2.1 Hz, 1H), 6.80 (d, J = 8.3Hz, 1H), 4.12 (s, 1H), 3.19 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 177.36 (s),141.94 (s), 139.54 (s), 133.38 (s), 129.69 (s), 128.96 (s), 128.72 (s,),128.53 (s), 125.50 (s), 125.26 (s), 109.72 (s), 78.02 (s), 26.65 (s).

[0039] 3-hydroxy-1-methyl-3-(thiophen-2-yl)indolin-2-one (2d): 1 H NMR (400MHz, CDCl3): δ 7.53 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 5.0 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 4 Hz, 1H), 6.96 – 6.91(t, 1H), 6.89 (d, J = 7.8 Hz, 1H), 3.49 (s, 1H), 3.23 (s, 3H).

[0040] 1-(but-2-yn-1-yl)-3-hydroxy-3-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (2e): 1 H NMR (400 MHz, CDCl3): δ 8.27 (dd, J = 5.3, 1.5 Hz, 1H), 7.52 (dd, J = 7.3, 1.5 Hz, 1H), 7.39 (dd, J = 7.9, 1.7 Hz, 2H), 7.37 – 7.28(m, 3H), 6.99 (dd, J = 7.3, 5.3 Hz, 1H), 4.56 (s, 2H), 4.11 (s, 1H), 1.78 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 176.62 (s), 155.60 (s), 148.68 (s), 139.27(s), 132.63 (s), 128.81 (s), 128.67 (s), 126.29 (s), 125.21 (s), 119.28 (s), 79.29 (s), 77.69 (s), 72.43 (s), 29.02 (s), 3.67 (s). Example 3

[0041] Weigh 36 mg of NaH (60% in oil, 0.9 mmol, 3.0 equiv) into a 10 mL sealed tube, add 1 mL of anhydrous 1,4-dioxane, and stir at room temperature for 5 min. Then add o-iodoaryl α-ketoamide 1f-1n (0.3 mmol, 1.0 equiv, dissolved in 1 mL of 1,4-dioxane), fill the sealed tube with N2, and react at 90 °C for 12 h. Then quench the reaction with saturated NH4Cl solution under ice bath conditions. Transfer the reaction solution to a separatory funnel, extract the aqueous phase three times with ethyl acetate, and finally combine the organic phases, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter, vacuum dry, and then purify and separate by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the corresponding product (2f-2n).

[0042] The different reaction substrates (o-iodoaryl α-ketoamides 1f-1n) and the resulting 3-hydroxy-2-indole ketone derivatives 2f-2n are shown in Table 3.

[0043] Table 3. Reactions of o-iodoaryl α-ketoamides 1f-1n

[0044]

[0045] The above product data are characterized as follows:

[0046] 3-(tert-butyl)-3-hydroxy-1-methylindolin-2-one(2f): 1 H NMR (400 MHz, CDCl3): δ 7.40 (dd, J = 7.4, 0.7 Hz, 1H), 7.31 (td, J = 7.7, 1.2 Hz, 1H), 7.05 (td, J = 7.6, 1.0 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 3.15 (s, 3H), 2.74 (s, 1H), 1.04 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 178.53 (s), 144.15 (s), 129.42 (s), 129.35 (s)125.66 (s), 122.27 (s), 107.93 (s), 80.95 (s), 37.76 (s), 26.04 (s), 23.91 (s).

[0047] 3,5-di-tert-butyl-3-hydroxy-1-methylindolin-2-one (2g): 1 H NMR (400MHz, CDCl3): δ 7.43 (s, 1H), 7.31 (dd, J = 8.1, 1.5 Hz, 1H), 6.70 (s, 1H), 3.14 (s, 3H), 2.92 (s, 1H), 1.32 (s, 9H), 1.03 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 178.66 (s), 145.32 (s), 141.63 (s), 129.17 (s), 125.64 (s), 123.06 (s), 107.22 (s), 81.18 (s), 37.73 (s), 34.51(s), 31.54(s), 26.02(s), 23.99(s).

[0048] 3-(tert-butyl)-3-hydroxy-1-methyl-5-(trifluoromethyl)indolin-2-one(2h): 1 H NMR (400 MHz, CDCl3): δ 7.62 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 6.88(d, J = 8.1 Hz, 1H), 3.19 (s, 3H), 1.03 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ178.53 (s), 147.07 (s), 130.07 (s), 127.07 (q, J = 4.0 Hz),124.59(q, J = 33.3Hz, 1H), 124.3(q, J = 272.7 Hz, 1H), 123.14 – 122.47 (q, J = 4.0 Hz), 107.68(s), 80.76 (s), 37.85 (s), 26.22 (s), 23.78 (s). 19 F NMR (377 MHz, CDCl3) δ -61.57 (s).

[0049] 3-(tert-butyl)-3-hydroxy-5-methoxy-1-methylindolin-2-one (2i): 1 H NMR(400 MHz, CDCl3): δ 7.03 (d, J = 2.5 Hz, 1H), 6.82 (dd, J = 8.5, 2.6 Hz, 1H),6.69 (d, J = 8.5 Hz, 1H), 3.79 (s, 3H), 3.12 (s, 3H), 3.01 (s, 1H), 1.03 (s,9H). 13 C NMR (101 MHz, CDCl3): δ 178.20 (s), 155.59 (s), 137.55 (s), 130.83(s), 113.45 (s), 113.38 (s), 108.11 (s), 81.25 (s), 55.84 (s), 37.74 (s),26.08 (s), 23.91 (s).

[0050] 3-(tert-butyl)-5-chloro-3-hydroxy-1-methylindolin-2-one(2j): 1 H NMR(400 MHz, CDCl3): δ 7.37 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.2, 1.9 Hz, 1H),6.72 (d, J = 8.3 Hz, 1H), 3.13 (s, 3H), 2.97 (s, 1H), 1.03 (s, 9H). 13 C NMR(101 MHz, CDCl3): δ 178.10 (s), 142.65 (s), 131.16 (s), 129.14 (s), 127.78(s), 126.19 (s), 108.81 (s), 81.04 (s), 37.82 (s), 26.15 (s), 23.84 (s).

[0051] 3-(tert-butyl)-3-hydroxy-1-methyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (2k): 1 H NMR (400 MHz, CDCl3): δ 8.17 (dd, J = 5.3, 1.5 Hz, 1H),7.61 (dd, J = 7.3, 1.5 Hz, 1H), δ 6.95 (dd, J = 7.3, 5.3 Hz, 1H), 3.25 (s,1H), 3.22 (s, 3H), 1.03 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 178.31 (s),157.37 (s), 147.91 (s), 132.93 (s), 124.30 (s), 117.88 (s), 80.75 (s), 37.88(s), 25.06 (s), 23.89 (s).

[0052] 3-(tert-butyl)-7-chloro-3-hydroxy-1-methylindolin-2-one (2l): 1 H NMR(400 MHz, CDCl3):δ 7.27 (dd, J = 7.4, 1.0 Hz, 1H), 7.22 (dd, J = 8.2, 1.1 Hz,1H), 6.95 (t, J = 8 Hz, 1H), 3.50 (s, 3H), 3.18 (s, 1H), 1.00 (s, 9H). 13 C NMR(101 MHz, CDCl3): δ 178.93 (s), 139.77 (s), 132.53 (s), 131.50 (s), 124.15(s), 122.92 (s), 115.31 (s), 80.44 (s), 37.98 (s), 29.40 (s), 23.87 (s).

[0053] 3-cyclopropyl-3-hydroxy-1-methylindolin-2-one (2m): 1 H NMR (400 MHz,DMSO):δ 7.18 (t, J = 8 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 6.88 (t, J = 8 Hz,1H), 6.83 (d, J = 7.8 Hz, 1H), 2.94 (s, 3H), 2.36 (s, 1H), 1.02 (tt, J = 8.3,5.2 Hz, 1H), 0.39 (td, J = 9.8, 5.4 Hz, 1H), 0.31 – 0.20 (m, 1H), 0.19 – 0.10(m, 1H), -0.01 (td, J= 9.6, 5.5 Hz, 1H). 13 C NMR (101 MHz, DMSO): δ 177.28(s), 143.00 (s), 130.89 (s), 128.99 (s), 123.59 (s), 122.01 (s), 108.29 (s),74.37 (s), 25.75 (s), 17.47 (s), 0.53 (s), -0.50 (s).

[0054] 3-(tert-butyl)-1-cyclopentyl-3-hydroxyindolin-2-one (2n): 1 H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 8 Hz, 1H), 7.25 (t, J = 6 Hz, 1H), 7.01 (t, J = 8 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 4.67 (p, J = 8.7 Hz, 1H), 2.94 (s,1H), 2.11 – 2.00 (m, 2H), 1.95 – 1.85 (m, 4H), 1.73 – 1.65 (m, 2H), 1.01 (s,9H). 13 C NMR (101 MHz, CDCl3): δ 178.32 (s), 142.60 (s), 129.89 (s), 128.85 (s), 125.89 (s), 121.64 (s), 109.36 (s), 80.49 (s), 52.27 (s), 37.93 (s), 27.95 (s), 26.90 (s), 25.13 (s), 23.92 (s).

[0055] Substrate 1 was prepared using conventional methods. Taking the preparation of 1a as an example, the specific method is as follows:

[0056]

[0057] At room temperature, aryl α-keto acid (5 mmol, 1.0 eq.) was dissolved in CH2Cl2 (10 mL), one drop of DMF was added as a catalyst, followed by the addition of oxaloyl chloride (6 mmol, 1.2 eq.), and the mixture was stirred at room temperature for 1 hour. After removing all volatiles under vacuum, the residue was dissolved in CH2Cl2 (10 mL), cooled to 0 °C, and N-methyl-o-iodoaniline (7.5 mmol, 1.5 eq.) and DIPEA (10 mmol, 2.0 eq.) were added. The reaction flask was placed at room temperature and stirred for 3 hours. The reaction was quenched with 15 mL of water, extracted three times with EA, the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, the solvent was evaporated, and column chromatography was performed to obtain 1a.

[0058] N-(2-iodophenyl)-N-methyl-2-oxo-2-phenylacetamide (1a) 1 H NMR (400MHz, CDCl3): δ 7.93 (d, 2H, J = 7.3 Hz), 7.81 (d, 1H, J = 7.6 Hz), 7.57 (dd, 1H, J = 7.3, 13.8 Hz), 7.43 (t, 2H, J = 7.8 Hz), 7.23-7.29 (m, 2H), 6.93-6.98(m, 1H), 3.29 (s, 3H).

[0059] This invention discloses a method for activating o-iodoaryl α-ketoamides with NaH. By guiding a Na-I exchange reaction between NaH and iodine, an intramolecular reaction is achieved, synthesizing 3-hydroxy-2-indolone derivatives. This invention has broad substrate applicability. Compared with traditional methods, this method can achieve metal-halogen exchange reactions that cannot be achieved with traditional strong bases in the presence of ketone carbonyl groups, completing intramolecular cyclization reactions. Furthermore, the operation is simple, the reaction conditions are mild, and no transition metal catalysis or strictly anhydrous conditions are required. This mode of synthesizing 3-hydroxy-2-indolones through the reaction of o-iodoaryl α-ketoamides and sodium hydride provides a new method for the synthesis of such substances and has broad application prospects.

Claims

1. A method for preparing 3-hydroxy-2-indolone compound, comprising the following steps: reacting o-iodo aryl α-ketoamide in a solvent in the presence of sodium hydride to obtain 3-hydroxy-2-indolone compound. The chemical structural formula of o-iodo aryl α-ketoamide is as follows: ； wherein Ar is a phenyl ring; R is phenyl or an aromatic heterocycle, t-butyl or cyclopropyl; R 1 is one or more of halogen, t-butyl, methoxy, trifluoromethyl; the aromatic heterocycle is a thiophene ring; R 2 is methyl, ethyl, propyl, isobutyl, n-pentyl, cyclobutyl or cyclopentyl; The chemical structural formula of the product 3-hydroxy-2-indolone compound is as follows: ； wherein Ar is a benzene ring; R is a phenyl group or an aromatic heterocycle, a tert-butyl group or a cyclopropyl group; R 1 is one or several of halogen, a tert-butyl group, a methoxy group, a trifluoromethyl group; the aromatic heterocycle is a thiophene ring; R 2 is a methyl group, an ethyl group, a propyl group, an isobutyl group, a n-pentyl group, a cyclobutyl group or a cyclopentyl group; The molar ratio of o-iodo aryl α-ketoamide to sodium hydride is 1: (2-5); the reaction temperature is 40-120℃, and the reaction time is 2-48 hours.

2. The method for preparing the 3-hydroxy-2-indolone compound according to claim 1, characterized in that, The reaction temperature is 80-100℃, and the reaction time is 10-15 hours.

3. The method for preparing the 3-hydroxy-2-indolone compound according to claim 1, characterized in that, The solvent is tetrahydrofuran or 1,4-dioxane.

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