Preparation method of 3-hydroxy-2-indolone compound

Abstract

The invention discloses a preparation method of a 3-hydroxy-2-indolone compound and a preparation method of the 3-hydroxy-2-indolone compound. O-iodoaryl alpha-ketoamide reacts with sodium hydride in a solvent, sodium hydride is activated and is subjected to Na-I exchange reaction with iodobenzene, then ketocarbonyl of alpha-ketoamide is attacked in an intramolecular nucleophilic mode, and a series of 3-hydroxy-2-indolone derivatives which are difficult to synthesize through other methods are prepared. The method is simple to operate and mild in reaction condition, no transition metal catalyst is needed, and the reaction provides a new, direct and efficient synthesis strategy for preparing the 3-hydroxy-2-indolone compound. The method for preparing the 3-hydroxy-2-indolone product disclosed by the invention has an application value in medicine synthesis.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for preparing 3-hydroxy-2-indolone from o-iodoaryl alpha-ketoamide through intramolecular cyclization. Background Art

[0002] 3-Hydroxy-2-indolinone is the core structure of many drugs and natural products with 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 trichloroacetate through an acid-catalyzed substitution reaction mediated by trichloroacetonitrile.

[0005] For example, 3-hydroxy-2-indolone was reacted with various aromatics and heteroaromatics via a Hg(ClO4)2·3H2O-catalyzed Friedel-Craft reaction to synthesize 3,3-disubstituted-2-indolone.

[0006]

[0007] The existing synthesis methods of 3-hydroxy-2-indolone include: using isatin as a raw material and reacting it with Grignard reagents, lithium reagents, etc.; or using α-ketoanilide as a raw material, under the action of phosphate, ligand and triethylamine, using palladium to activate the aromatic trifluorate (or other halogen) in the molecule to achieve the addition cyclization of the keto group in the molecule. However, the palladium catalyst is expensive, the reaction temperature is high and the reaction time is long, which reduces the practical value of this method.

[0008]

[0009] In summary, the existing methods for synthesizing 3-hydroxy-2-indolone either require highly active reagents and harsh reaction conditions, or require precious metal catalysis, which is costly and has the risk of heavy metal residues in the product. Therefore, it is necessary to develop a new method that can start from simple raw materials, use cheap initiating reagents, and achieve the preparation of 3-hydroxy-2-indolone compounds under milder conditions. Summary of the invention

[0010] The present invention discloses a method for synthesizing a 3-hydroxy-2-indolone compound from an ortho-iodoaryl α-ketoamide, wherein a commercially available 60% NaH mineral oil dispersion is used to initiate the reaction; the method of the present invention is simple to operate, has mild reaction conditions, does not require transition metal catalysis and strict anhydrous conditions, and is easy to prepare on a large scale. The method adopts a new technical idea, activates the nucleophilic activity of NaH, initiates Na-I exchange, and attacks the ketone carbonyl intramolecularly, and finally obtains the cyclization product 3-hydroxy-2-indolone. The present invention solves the problems of harsh conditions, high reagent prices, heavy metal residues, etc. when such products are prepared using traditional methods.

[0011] The present invention adopts the following technical solution: A method for preparing a 3-hydroxy-2-indolone compound comprises the following steps: reacting o-iodoaryl α-ketoamide in a solvent in the presence of sodium hydride to obtain the 3-hydroxy-2-indolone compound.

[0012] In the present invention, the molar ratio of o-iodoaryl α-ketoamide to sodium hydride is 1:(2-5), preferably 1:3.

[0013] In the present 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.

[0014] In the present invention, the solvent is tetrahydrofuran or 1,4-dioxane, preferably 1,4-dioxane.

[0015] In the present invention, the chemical structural formula of the o-iodoaryl α-ketoamide is as follows:

[0016] The chemical structure of the product 3-hydroxy-2-indolone compound is as follows:

[0017] Wherein, Ar is a benzene ring or a heterocyclic ring, such as a pyridine ring; R is a substituted phenyl or aromatic heterocyclic ring, tert-butyl, cyclopropyl, etc.; R 1 is halogen, tert-butyl, methoxy, trifluoromethyl, etc.; R 2 It is various straight-chain alkanes, branched-chain alkanes, and cycloalkanes, such as methyl, ethyl, propyl, isobutyl, n-pentyl, cyclobutyl, cyclopentyl, and the like.

[0018] The prior art uses ortho-halogen (or OTf) aromatic α-ketoamide as raw material, uses transition metal catalysis to preferentially attack ketone carbonyl, and then performs intramolecular reaction to achieve the synthesis of 3-hydroxy-2-indolone compounds. The catalyst is expensive and the reaction conditions are relatively harsh. The present invention discloses for the first time a method using sodium hydride as an activator, adopts a new technical idea, and obtains 3-hydroxy-2-indolone compounds through Na-I exchange reaction and intramolecular addition to ketone carbonyl. The method of the present invention is carried out under relatively mild reaction conditions, is simple to operate, does not require any transition metal catalysis or strict anhydrous conditions, and is difficult to achieve such a conversion using traditional methods such as Grignard reagents, alkyl lithium, and amide lithium. Therefore, the present invention is a new method that can start from simple raw materials, use cheap initiating reagents, and achieve the preparation of 3-hydroxy-2-indolone compounds under relatively mild conditions. DETAILED DESCRIPTION

[0019] The present invention uses o-iodine aryl α-ketoamide as a raw material, and reacts in a solvent in the presence of an alkaline metal hydride sodium hydride to obtain a 3-hydroxy-2-indolone compound, without the need for a Grignard reagent, a metal, or a metal compound catalyst. Specifically, NaH is weighed in a sealed tube, anhydrous 1,4-dioxane is added, and a 1,4-dioxane solution of o-iodine aryl α-ketoamide is added under stirring, nitrogen is filled into the sealed tube, and the reaction is carried out at 90°C for 12 hours to obtain a 3-hydroxy-2-indolone derivative.

[0020] In order to more clearly understand the technical content of the present invention, the following examples are given in detail. All raw materials are commercially available products or prepared according to literature methods, and the specific operations and testing methods are conventional techniques.

[0021] NMR spectrum 1 H NMR and 13 C NMR was measured using Agilent 400 MHz and Bruker 400 MHz instruments, and the sample solvent was CDCl3 (7.26 ppm). The NMR data report includes: chemical shift, peak area integration, coupling constant, peak shape, etc. TLC thin layer chromatography plates were produced by Yantai Huanghai Chemical Plant, with visual monitoring at 254 nm and 365 nm wavelengths, and the silica gel mesh used for rapid column chromatography was 200-300 mesh. All reagents used were commercially available analytical or chemically pure, and were used directly without special instructions. Anhydrous solvents were all redistilled solvents or commercially available dry solvents (B&K). Embodiment 1

[0022] NaH (60% in oil) was weighed into a sealed tube, anhydrous 1,4-dioxane was added, and after stirring at room temperature for 5 min, o-iodoaryl α-ketoamide 1a was added, N2 was filled into the sealed tube, and the reactants were placed at 90°C for 12 h, and then saturated NH4Cl solution was added to quench under ice bath conditions. The aqueous phase was extracted with ethyl acetate three times, the organic phases were combined, washed with saturated NaCl solution, dried by adding anhydrous Na2SO4, filtered, and dried under vacuum, and then purified and separated by silica gel column to obtain the corresponding product 2a with a yield of 48%.

[0023] The reaction results under different operating conditions are shown in Table 1.

[0024] Table 1 Results under different reaction conditions

[0025] Embodiment 2

[0026] Weigh NaH (36 mg, 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 1b-1e (0.3 mmol, 1.0 equiv, dissolved in 1 mL 1,4-dioxane) in sequence, fill the sealed tube with N2, react at 90 °C for 12 h, then add saturated NH4Cl solution to quench under ice bath, transfer the reaction solution to a separatory funnel, extract the aqueous phase with ethyl acetate three times, and finally combine the organic phases, wash with saturated NaCl solution, add anhydrous Na2SO4 to dry, filter, vacuum dry, and then purify and separate on a silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain the corresponding products (2b-2e).

[0027] The corresponding reaction substrates (o-iodoaryl α-ketoamides 1a-1e) and the obtained 3-hydroxy-2-indolone derivatives 2a-2e are shown in Table 2.

[0028] Table 2 Reactions of o-iodoaryl α-ketoamides 1a-1e The above product data are characterized as follows: 3-hydroxy-1-methyl-3-phenylindolin-2-one (2a): 1 H 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. 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). 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). 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). 1-(but-2-yn-1-yl)-3-hydroxy-3-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (2e): 1H 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). Embodiment 3

[0029] Weigh NaH (36 mg, 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 1,4-dioxane), fill the sealed tube with N2, react at 90 °C for 12 h, then add saturated NH4Cl solution to quench under ice bath, transfer the reaction solution to a separatory funnel, extract the aqueous phase with ethyl acetate three times, and finally combine the organic phases, wash with saturated NaCl solution, add anhydrous Na2SO4 to dry, filter, vacuum dry, and then purify and separate on a silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain the corresponding products (2f-2n).

[0030] The corresponding reaction substrates (o-iodoaryl α-ketoamides 1f-1n) and the obtained 3-hydroxy-2-indolone derivatives 2f-2n are shown in Table 3.

[0031] Table 3 Reaction of o-iodoaryl α-ketoamide 1f-1n

[0032] The above product data are characterized as follows: 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). 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). 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). 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). 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). 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). 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). 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). 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). Substrate 1 is prepared according to a general conventional method. Taking the preparation of 1a as an example, the specific method is as follows:

[0033] Aryl α-keto acid (5 mmol, 1.0 eq.) was dissolved in CH2Cl2 (10 mL) at room temperature, and a drop of DMF was added as a catalyst. Oxalyl chloride (6 mmol, 1.2 eq.) was then added dropwise, and the mixture was stirred at room temperature for 1 hour. After all volatiles were removed by 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 allowed to cool to room temperature and stirred for 3 h. The reaction was quenched by adding 15 mL of water, extracted three times with EA, and the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, the solvent was spin-dried, and column chromatography was performed to obtain 1a.

[0034] 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). The invention discloses a method for activating o-iodine aryl α-ketoamide with NaH, and synthesizes 3-hydroxy-2-indolone derivatives by guiding NaH and iodine to carry out Na-I exchange reaction and realize intramolecular reaction. The invention has wide substrate applicability. Compared with the traditional method, the method of the invention can realize the metal-halogen exchange reaction that the traditional strong base cannot realize in the presence of keto carbonyl, and complete the intramolecular cyclization reaction; and the operation is simple, the reaction conditions are mild, and no transition metal catalysis and strict anhydrous conditions are required. This mode of synthesizing 3-hydroxy-2-indolone by the action of o-iodine aryl α-ketoamide and sodium hydride provides a new method for the synthesis of such substances, and has broad application prospects.

Claims

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

2. The method for preparing the 3-hydroxy-2-indolone compound according to claim 1, characterized in that: The molar ratio of o-iodoaryl α-ketoamide and sodium hydride is 1:(2-5).

3. The method for preparing the 3-hydroxy-2-indolone compound according to claim 1, characterized in that: The reaction temperature is 40 to 120° C. and the reaction time is 2 to 48 hours.

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

5. 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.

6. The method for preparing the 3-hydroxy-2-indolone compound according to claim 1, characterized in that: The chemical structure of o-iodoaryl α-ketoamide is as follows: ； Wherein, Ar is a benzene ring or a heterocyclic ring; R is a substituted phenyl or aromatic heterocyclic ring, tert-butyl or cyclopropyl; R 1 is one or more of halogen, tert-butyl, methoxy, and trifluoromethyl; R 2 It is a straight-chain alkane, a branched-chain alkane or a cycloalkane.

7. The method for preparing the 3-hydroxy-2-indolone compound according to claim 1, characterized in that: The chemical structure of the product 3-hydroxy-2-indolone compound is as follows: ； Wherein, Ar is a benzene ring or a heterocyclic ring; R is a substituted phenyl or aromatic heterocyclic ring, tert-butyl or cyclopropyl; R 1 is one or more of halogen, tert-butyl, methoxy, and trifluoromethyl; R 2 It is a straight-chain alkane, a branched-chain alkane or a cycloalkane.

8. The method for preparing the 3-hydroxy-2-indolone compound according to claim 6 or 7, characterized in that: Heterocyclic rings include pyridine rings; aromatic heterocyclic rings include thiophene rings; R 2 It is methyl, ethyl, propyl, isobutyl, n-pentyl, cyclobutyl or cyclopentyl.

9. The 3-hydroxy-2-indolone compound prepared according to the method for preparing the 3-hydroxy-2-indolone compound according to claim 1.

10. Application of o-iodoaryl α-ketoamide and sodium hydride in the preparation of 3-hydroxy-2-indolone compounds.

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