A preparation method of indole spiroisochromanone derivatives

Abstract

The invention discloses a method for preparing an indole spiroisochromanone derivative, and belongs to the technical field of organic synthesis. The specific method is: using an indole derivative containing an aromatic carboxylic acid as a substrate, using iodine as an oxidant, and using water as a solvent, stirring and reacting to obtain an indole spiroisochromanone derivative; the structural formula of the indole derivative containing an aromatic carboxylic acid is: #imgabs0#; the structural formula of the indole spiroisochromanone derivative is: #imgabs1#; wherein R 1 is hydrogen, fluorine, bromine, methyl or methoxy; R 2 is methyl, allyl or benzyl; R 3 The present invention prepares the indole spiroisochromanone derivative via an iodonium ion intermediate through intramolecular nucleophilic substitution, hydrolysis, oxidation and the like. The preparation method of the present invention is not dependent on peroxides, is mild, green, simple, efficient, safe and low in cost.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing an indole spiroisochromanone derivative. Background Art

[0002] Spirocyclic indole derivatives are widely present in many natural products and drug molecules, and have rich biological and pharmaceutical activities, such as anti-cancer, anti-tumor, anti-HIV, anti-diabetes, anti-malarial, anti-inflammatory, anti-tuberculosis, antibacterial, antiviral and antifungal activities (Org. Biomol. Chem., 2017, 15, 2711; Green Synth. Catal., 2024, 5, 1). Indole spiroisochromanone is one of the indole spironolactone compounds, and its analogues are more common in some biologically active molecules. Therefore, synthetic chemists and pharmacists have been actively studying new methods for the efficient synthesis of such compounds.

[0003] In recent years, iodine-mediated or catalyzed oxidative coupling reactions have attracted widespread attention from chemists and pharmacists as a metal-free strategy. This is because the methods involved usually have many advantages such as mild reaction conditions and simple experimental operations, providing a common and effective means for the green and efficient construction of some pharmaceutical intermediates and bioactive molecular skeletons (ChemCatChem, 2012, 4, 177; Chem. Rec., 2018, 18, 1292; Asian J. Org. Chem., 2021, 10, 2503). At present, there are only a few reports on the iodine-mediated synthesis of indole spiroisochromanone derivatives under metal-free conditions: Zhong Fangrui et al. used indole-derived aromatic carboxylic acids as substrates, dodecyltrimethylammonium iodide as catalysts and surfactants, and peroxide as oxidant to prepare spirocyclic indole ketone compounds through intramolecular carbonyl α-position oxidative coupling reaction in aqueous phase (Eur. J. Org. Chem., 2019, 6028; CN201910142070.3). However, this method has the following shortcomings: (1) It is necessary to prepare the substrate with substituted indigo carmine as the initial raw material, the synthetic route is complicated, the step economy is poor, and the post-processing is relatively cumbersome; (2) It relies on the use of stoichiometric peroxide (30% hydrogen peroxide) and needs to be heated at 60°C, and the safety needs to be improved. According to my country's "List of Dangerous Chemicals that Can Make Explosives (2017 Edition)", hydrogen peroxide with a concentration of more than 8% is a dangerous chemical (easy to make explosives) and is subject to control and needs to be stored and used with caution. Wang Rui et al. reported a method for preparing indole spironolactone compounds, using 3-indolepropionic acid derivatives as substrates, NaI as catalysts, H2O2 as oxidants, and acetonitrile as solvents, and stirred the reaction at room temperature to prepare indole quinoline compounds (Adv. Synth. Catal., 2016, 358, 2873). The reaction relies on the use of stoichiometric peroxides and organic solvents as reaction media, and there is still much room for improvement from the perspective of green chemistry. In terms of the scope of substrate application, this method is limited to the preparation of indole spironolactone derivatives. If you want to obtain indole spironolactones of other structures (such as indole spiroisochromanone), this method is difficult to achieve. The patent with application number CN202111283033.8 discloses a method for preparing chiral spirocyclic indolinone compounds, which uses indolinone-derived compounds containing active hydrogen functional groups as raw materials, cinchona alkali-derived quaternary ammonium iodide salts as catalysts, and peroxides as oxidants, and prepares chiral spirocyclic indolinone compounds through intramolecular carbonyl α-asymmetric oxidative coupling reactions in organic solvents. This method also uses peroxide as an oxidant and indolinone as a reaction substrate for the reaction. In addition, the solvent of the reaction is an organic solvent, which is not green and safe enough compared to water as a solvent.

[0004] Although there have been reports on the synthesis of indolone spiroisochromanone compounds mediated or catalyzed by iodine under metal-free conditions, most existing preparation methods use indolone or isatin derivatives as raw materials, with complex synthetic routes and rely on the use of peroxides or organic solvents. Some reactions even require heating in the presence of peroxides. Therefore, there is an urgent need for a safe, low-cost, mild and green method that does not rely on peroxides to synthesize indolone spiroisochromanone derivatives more simply and efficiently. Summary of the invention

[0005] In view of the above-mentioned prior art, the purpose of the present invention is to provide a method for preparing an indole spiroisochromanone derivative. The present invention uses an indole derivative containing an aromatic carboxylic acid as a substrate, iodine as an oxidant, and water as a solvent, and stirs the reaction at room temperature to prepare an indole spiroisochromanone derivative. The preparation method of the present invention does not rely on peroxides, is mild, green, simple, efficient, safe, and low in cost.

[0006] To achieve the above object, the present invention adopts the following technical solution:

[0007] The present invention provides a method for preparing an indole spiroisochromanone derivative, the preparation method comprising:

[0008] An indole derivative containing an aromatic carboxylic acid is used as a substrate, iodine is used as an oxidant, and water is used as a solvent, and the reaction is stirred to obtain an indole spiroisochromanone derivative;

[0009] The structural formula of the indole derivative containing aromatic carboxylic acid is:

[0010] ;

[0011] The structural formula of the indole spiroisochromanone derivative is:

[0012] ;

[0013] Among them, R 1 is hydrogen, fluorine, bromine, methyl or methoxy; R 2 is methyl, allyl or benzyl; R 3 is hydrogen or chlorine.

[0014] Preferably, the molar ratio of the substrate to the oxidant is 1:2.

[0015] Preferably, the ratio of the added amount of the substrate to the added amount of the solvent is 1 mmol:10 mL.

[0016] Preferably, the stirring reaction temperature is 20-40°C.

[0017] Preferably, the stirring reaction temperature is 25°C.

[0018] Preferably, the stirring reaction time is 4 to 96 hours.

[0019] Preferably, the stirring reaction time is 24 hours.

[0020] After the reaction is completed, the product needs to be purified: saturated sodium thiosulfate solution is added for quenching, the mixed solution is extracted with ethyl acetate, the organic phases are combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the product is purified by column chromatography.

[0021] Beneficial effects of the present invention:

[0022] (1) The present invention uses an indole derivative containing an aromatic carboxylic acid as a substrate, iodine as an oxidant, and water as a solvent, and reacts under stirring at room temperature to obtain an indole spiroisochromanone derivative. The starting materials involved in the preparation method are all industrial products, which are easy to obtain and have a wide range of sources.

[0023] (2) The method provided by the present invention does not require indole ketone or isatin derivatives as raw materials, can completely avoid the addition of any peroxide and organic solvent during the reaction, and can be carried out smoothly at room temperature. It has the characteristics of easy preparation of raw materials, mild reaction conditions, simple operation, good functional group tolerance, and easy expansion of reaction scale, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 1;

[0025] Figure 2 The carbon NMR spectrum of the target product obtained in Example 1;

[0026] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 2;

[0027] Figure 4 is the carbon NMR spectrum of the target product obtained in Example 2;

[0028] Figure 5 is the nuclear magnetic resonance fluorine spectrum of the target product obtained in Example 2;

[0029] Figure 6 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 3;

[0030] Figure 7 The carbon NMR spectrum of the target product obtained in Example 3;

[0031] Figure 8 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 4;

[0032] Fig. 9 The carbon NMR spectrum of the target product obtained in Example 4;

[0033] Fig.10 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 5;

[0034] Fig.11 This is the carbon NMR spectrum of the target product obtained in Example 5;

[0035] Fig.12 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 6;

[0036] Fig.13 is the carbon NMR spectrum of the target product obtained in Example 6;

[0037] Fig.14 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 7;

[0038] Fig.15 is the carbon NMR spectrum of the target product obtained in Example 7;

[0039] Fig.16 is the hydrogen nuclear magnetic resonance spectrum of the target product obtained in Example 8;

[0040] Fig.17 This is the carbon NMR spectrum of the target product obtained in Example 8. DETAILED DESCRIPTION

[0041] It should be noted that the following detailed descriptions are illustrative and are intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present application belongs.

[0042] As introduced in the background technology section, the current iodine-mediated synthesis of indolinone spiroisochromanone derivatives mostly uses indolinone or isatin derivatives as raw materials and relies on the use of peroxides or organic solvents. Some reactions even require heating in the presence of peroxides, and there are also technical problems with limitations in the step economy and safety of the reaction.

[0043] Based on this, the purpose of the present invention is to provide a method for preparing an indole spiroisochromanone derivative. In addition to not requiring the use of a catalyst, the preparation method of the present invention does not use peroxide as an oxidant, and the reaction substrate is not indole, but an indole compound. The present invention uses an indole derivative containing an aromatic carboxylic acid as a substrate, iodine as an oxidant, and water as a solvent, and stirs the reaction at room temperature to obtain an indole spiroisochromanone derivative. The general reaction formula is:

[0044] .

[0045] In the above reaction, the indole spiroisochromanone derivative is prepared through the iodonium ion intermediate, through intramolecular nucleophilic substitution, hydrolysis, oxidation and other steps. The reaction mechanism is speculated to be the following two:

[0046] .

[0047] It can be seen that in the above two possible reaction principles, water is not only used as a solvent, but also as a source of carbon groups in indolone, providing oxygen atoms for the reaction, thereby realizing the preparation of indolone from indole. Indole derivatives containing aromatic carboxylic acids show hydrophobicity in the solvent water, and the oxidant iodine is also a hydrophobic reagent. Using water as a solvent increases the interaction between the hydrophobic substrate and the iodine element, increases the probability of effective collision between molecules, and promotes the improvement of the reaction rate and yield.

[0048] In order to enable those skilled in the art to more clearly understand the technical solution of the present application, the technical solution of the present application will be described in detail below in conjunction with specific embodiments.

[0049] Note: The water used in the examples is distilled water, and the effect of other water on the reaction has not been tested.

[0050] The indole raw materials used in the examples are all prepared by three-step reactions: (1) indole containing different substituents on the benzene ring is first subjected to a substitution reaction with an alkyl halide, so that the indole nitrogen atom is protected by an alkyl group; (2) the product of step (1) is then subjected to a condensation reaction with methyl 2-formylbenzoate, so that the indole is connected to methyl formate with a benzene ring; (3) finally, methyl formate is hydrolyzed to form formic acid, to obtain indole derivatives containing aromatic carboxylic acids with different substituents, which are used as reaction raw materials to prepare indole spiroisochromanone derivatives. The above three-step methods are all prepared with reference to existing preparation methods.

[0051] The test materials used in the examples of the present invention are all conventional test materials in the art and can be purchased through commercial channels.

[0052] Example 1: Preparation of 1-methylspiro[indoline-3,3'-isochromane]-1',2-dione

[0053] The specific synthetic route is:

[0054] .

[0055] The specific preparation process is:

[0056] (1) Using N-methylindole as the raw material, 2-[(6-fluoro-1-methyl-1 H Synthesis of 2-[(1-methyl-1-indol-3-yl)methyl]benzoic acid H-indol-3-yl)methyl]benzoic acid.

[0057] (2) Add 2-[(1-methyl-1 H 4-indol-3-yl)methyl]benzoic acid (0.2 mmol, 53.0 mg), 2 mL of water, and iodine (0.4 mmol, 101.6 mg) were stirred at room temperature for 24 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 4:1).

[0058] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then the mixed solution was extracted with ethyl acetate (5 mL*4), the organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 4:1 volume ratio), and a white solid product was obtained, namely 1-methylspiro[indoline-3,3'-isochromane]-1',2-dione, with a yield of 86%. Its nuclear magnetic resonance hydrogen spectrum is as follows Figure 1 As shown, the carbon NMR spectrum is Figure 2 The specific spectrum analysis data are as follows:

[0059] 1 H NMR (600 MHz, CDCl3) δ 8.19 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 7.5 Hz,1H), 7.48 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H),6.95 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 3.55(d, J = 16.6 Hz, 1H), 3.29 (d, J = 16.6 Hz, 1H), 3.20 (s, 3H).

[0060] 13C NMR (151 MHz, CDCl3) δ 172.4 (s), 163.8 (s), 143.4 (s), 136.0 (s), 134.3 (s), 131.1 (s), 130.2 (s), 128.3 (s), 128.1 (s), 127.4(s), 125.1 (s), 124.1 (s), 123.4 (s), 109.0 (s), 80.5 (s), 34.2 (s), 26.6 (s).

[0061] Example 2: Preparation of 6-fluoro-1-methylspiro[indoline-3,3'-isochromane]-1',2-dione

[0062] The specific synthetic route is:

[0063] .

[0064] The specific preparation process is:

[0065] (1) At room temperature, add 6-fluoroindole (10 mmol, 1.35 g) to a 100 mL flask equipped with a magnetic rod and dissolve it in 15 mL DMF. Add 60% NaH suspension (11 mmol, 0.44 g, dissolved in 25 mL DMF) dropwise and stir for 30 min. The mixture is cooled to 0°C, iodomethane (11 mmol, 685 μL) is added dropwise, stirred at room temperature overnight, and the reaction progress is monitored by thin layer chromatography. After the conversion of the raw material is completed, extract it with ethyl acetate three times, combine the organic phases and wash them with saturated NaCl, dry the organic phases over anhydrous Na2SO4, and concentrate under reduced pressure to obtain the crude product. Purify it by column chromatography to obtain 6-fluoro-1-methyl-1 H -Indole.

[0066] In a 50 ml flask equipped with a magnetic pole, add 6-fluoro-1-methyl-1 H-indole (5 mmol, 755 mg), methyl 2-formylbenzoate (5 mmol, 694 μL) and 10 mL CH2Cl2 were added. The mixture was then stirred and cooled to 0°C, and triethylsilane Et3SiH (14.82 mmol, 2.34 mL) and trifluoroacetic acid (9.9 mmol, 754 μL) were added in sequence. The mixture was stirred at 0°C for 15 min, then gradually warmed to room temperature and stirred for several hours. The reaction progress was monitored by thin layer chromatography. After the conversion of the raw materials was completed, the reaction was quenched with water and extracted with CH2Cl2 three times. The organic phases were combined and washed with saturated NaHCO3 and NaCl solutions. The organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. Column chromatography was used for purification to obtain methyl 2-[(6-fluoro-1-methyl-1H-indol-3-yl)methyl]benzoate.

[0067] In a 50 ml flask equipped with a magnetic pole, 2-[(6-fluoro-1-methyl-1 H 6-fluoro-1-methyl-1-[(6-fluoro-1-methyl-1-yl)methyl]benzoic acid methyl ester (2 mmol, 594 mg) and KOH (22.53 mmol, 894 mg) were dissolved in 14 mL of a mixed solution (MeOH:THF:H2O volume ratio = 5:1:1), stirred at room temperature for several hours, and the reaction progress was monitored by thin layer chromatography. After the conversion of the raw materials, the mixture was concentrated under reduced pressure, and the pH of the mixture was adjusted to 1 with 1M hydrochloric acid, and the crude product was obtained by suction filtration. Column chromatography was used for purification to obtain 2-[(6-fluoro-1-methyl-1 H -indol-3-yl)methyl]benzoic acid.

[0068] (2) Add 2-[(6-fluoro-1-methyl-1 H -indol-3-yl)methyl]benzoic acid (0.2 mmol, 56.6 mg), 2 mL of water, iodine (0.4 mmol, 101.6 mg), stirred at room temperature for 24 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 4:1).

[0069] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then the mixed solution was extracted with ethyl acetate (5 mL*4), the organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 4:1 volume ratio), and a white solid product was obtained, namely 6-fluoro-1-methylspiro[indoline-3,3'-isochromane]-1',2-dione, with a yield of 81%. Its nuclear magnetic resonance hydrogen spectrum is as follows Figure 3 As shown, the carbon NMR spectrum is Figure 4 As shown, the NMR fluorine spectrum is Figure 5 The specific spectrum analysis data are as follows:

[0070] 1 H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.1 Hz,1H), 7.50 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 5.7 Hz, 1H), 6.86 (dd, J = 8.0, 5.3 Hz,1H), 6.70 – 6.55 (m, 2H), 3.54 (d, J = 16.6 Hz, 1H), 3.28 (d, J = 16.6 Hz, 1H), 3.19 (s, 3H).

[0071] 13 C NMR (101 MHz, CDCl3) δ 167.1 (s), 137.5 (s), 133.2 (s), 132.3 (q, J = 32.3 Hz), 131.8 (s), 129.3 (s), 124.7 (s), 123.8 (q, J = 272.9 Hz), 72.3 (s), 47.0 (s), 23.4 (s), 20.8 (s).

[0072] 19 F NMR (565 MHz, CDCl3) δ -107.14 – -107.27 (m).

[0073] Example 3: Preparation of 7-bromo-1-methylspiro[indoline-3,3'-isochromane]-1',2-dione

[0074] The specific synthetic route is:

[0075] .

[0076] The specific preparation process is:

[0077] (1) Using 7-bromoindole as the raw material, 2-[(6-fluoro-1-methyl-1 H Synthesis of 2-[(7-bromo-1-methyl-1-indol-3-yl)methyl]benzoic acid H-indol-3-yl)methyl]benzoic acid.

[0078] (2) Add 2-[(7-bromo-1-methyl-1 H -indol-3-yl)methyl]benzoic acid (0.2 mmol, 68.6 mg), 2 mL of water, iodine (0.4 mmol, 101.6 mg), stirred at room temperature for 24 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 4:1).

[0079] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then the mixed solution was extracted with ethyl acetate (5 mL*4), the organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 4:1 volume ratio), and a white solid product was obtained, namely 7-bromo-1-methylspiro[indoline-3,3'-isochromane]-1',2-dione, with a yield of 82%. Its nuclear magnetic resonance hydrogen spectrum is as follows Figure 6 As shown, the carbon NMR spectrum is Figure 7 The specific spectrum analysis data are as follows:

[0080] 1 H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 7.7 Hz, 1H), 7.59 (td, J = 7.5, 1.1Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.23 (d, J = 7.5 Hz, 1H), 6.97 (dd, J = 7.4, 1.0Hz, 1H), 6.84 (t, J = 7.8 Hz, 1H), 3.56 (s, 3H), 3.45 (d, J = 16.7 Hz, 1H), 3.35(d, J = 16.7 Hz, 1H).

[0081] 13C NMR (101 MHz, CDCl3) δ 173.2 (s), 163.5 (s), 140.8 (s), 136.7 (s), 135.5 (s), 134.4 (s), 130.4 (s), 130.2 (s), 128.4 (s), 128.0 (s), 124.9 (s), 124.6 (s), 123.3 (s), 103.2 (s), 79.7 (s), 34.5 (s), 30.2 (s).

[0082] Example 4: Preparation of 1,7-dimethylspiro[indoline-3,3'-isochromane]-1',2-dione

[0083] The specific synthetic route is:

[0084] .

[0085] The specific preparation process is:

[0086] (1) Using 7-methylindole as the raw material, 2-[(6-fluoro-1-methyl-1 H Synthesis of 2-[(1,7-dimethyl-1-indol-3-yl)methyl]benzoic acid H -indol-3-yl)methyl]benzoic acid.

[0087] (2) Add 2-[(1,7-dimethyl-1 H -indol-3-yl)methyl]benzoic acid (0.2 mmol, 55.8 mg), 2 mL of water, iodine (0.4 mmol, 101.6 mg), stirred at room temperature for 24 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 4:1).

[0088] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then the mixed solution was extracted with ethyl acetate (5 mL*4), the organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 4:1 volume ratio), and a white solid product was obtained, namely 1,7-dimethylspiro[indoline-3,3'-isochromane]-1',2-dione, with a yield of 61%. Its nuclear magnetic resonance hydrogen spectrum is as follows Figure 8 As shown, the carbon NMR spectrum is Fig. 9 The specific spectrum analysis data are as follows:

[0089] 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.7 Hz, 1H), 7.58 (td, J = 7.5, 1.3Hz, 1H), 7.47 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.13 – 7.05 (m, 1H), 6.91 – 6.81 (m, 2H), 3.50 – 3.41 (m, 4H), 3.33 (d, J = 16.7 Hz, 1H), 2.56 (s, 3H).

[0090] 13 C NMR (101 MHz, CDCl3) δ 173.4 (s), 164.0 (s), 141.0 (s), 136.0 (s), 134.8 (s), 134.2 (s), 130.1 (s), 128.2 (s), 128.1 (s), 128.0 (s), 125.1 (s), 123.4 (s), 122.1 (s), 120.7 (s), 80.0 (s), 35.0 (s), 30.0 (s), 19.1 (s).

[0091] Example 5: Preparation of 5-methoxy-1-methylspiro[indoline-3,3'-isochromane]-1',2-dione

[0092] The specific synthetic route is:

[0093] .

[0094] The specific preparation process is:

[0095] (1) Using 5-methoxyindole as the raw material, 2-[(6-fluoro-1-methyl-1 H Synthesis of 2-[(5-methoxy-1-methyl-1 H -indol-3-yl)methyl]benzoic acid.

[0096] (2) Add 2-[(5-methoxy-1-methyl-1 H-indol-3-yl)methyl]benzoic acid (0.2 mmol, 59.0 mg), 2 mL of water, iodine (0.4 mmol, 101.6 mg), stirred at room temperature for 24 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 4:1).

[0097] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then the mixed solution was extracted with ethyl acetate (5 mL*4), the organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 4:1 volume ratio), and a white solid product was obtained, namely 5-methoxy-1-methylspiro[indoline-3,3'-isochromane]-1',2-dione, with a yield of 85%. Its nuclear magnetic resonance hydrogen spectrum is as follows Fig.10 As shown, the carbon NMR spectrum is Fig.11 The specific spectrum analysis data are as follows:

[0098] 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.7 Hz, 1H), 7.59 (t, J = 7.4 Hz,1H), 7.47 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 6.86 (dd, J = 8.5, 2.3 Hz,1H), 6.77 (d, J = 8.5 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 3.66 (s, 3H), 3.53 (d, J =16.6 Hz, 1H), 3.27 (d, J = 16.6 Hz, 1H), 3.16 (s, 3H).

[0099] 13C NMR (151 MHz, CDCl3) δ 172.2 (s), 163.7 (s), 156.3 (s), 136.6 (s), 135.9 (s), 134.33 (s), 130.1 (s), 128.4 (s), 128.3 (s), 128.1 (s), 125.0 (s), 115.1 (s), 111.7 (s), 109.5 (s), 80.8 (s), 55.8 (s), 34.2 (s), 26.6 (s).

[0100] Example 6: Preparation of 1-allylspiro[indoline-3,3'-isochromane]-1',2-dione

[0101] The specific synthetic route is:

[0102] .

[0103] The specific preparation process is:

[0104] (1) Using indole and 3-bromopropylene as raw materials, 2-[(6-fluoro-1-methyl-1 H Synthesis of 2-[(1-allyl-1-indol-3-yl)methyl]benzoic acid H -indol-3-yl)methyl]benzoic acid.

[0105] (2) Add 2-[(1-allyl-1 H -indol-3-yl)methyl]benzoic acid (0.2 mmol, 58.3 mg), 2 mL of water, iodine (0.4 mmol, 101.6 mg), stirred at room temperature for 24 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 4:1).

[0106] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then the mixed solution was extracted with ethyl acetate (5 mL*4), the organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 4:1 volume ratio), and a colorless oily product was obtained, namely 1-allyl spiro[indoline-3,3'-isochromane]-1',2-dione, with a yield of 74%. Its nuclear magnetic resonance hydrogen spectrum is as follows Fig.12 As shown, the carbon NMR spectrum is Fig.13 The specific spectrum analysis data are as follows:

[0107] 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.6 Hz, 1H), 7.60 (td, J = 7.5, 1.0Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.31 (td, J = 7.7, 1.4 Hz, 1H), 7.26 (d, J = 7.5Hz, 1H), 6.97 – 6.88 (m, 2H), 6.86 (d, J = 7.9 Hz, 1H), 5.91 – 5.74 (m, 1H), 5.29 – 5.23 (m, 2H), 4.37 – 4.24 (m, 2H), 3.57 (d, J = 16.6 Hz, 1H), 3.30 (d, J =16.6 Hz, 1H).

[0108] 13 C NMR (151 MHz, CDCl3) δ 172.2 (s), 163.8 (s), 142.5 (s), 135.9 (s), 134.4 (s), 131.0 (s), 130.7 (s), 130.2 (s), 128.3 (s), 128.1 (s), 127.3 (s), 125.0 (s), 124.1 (s), 123.4 (s), 118.4 (s), 109.9 (s), 80.5 (s), 42.7 (s), 34.3 (s).

[0109] Example 7: Preparation of 1-benzylspiro[indoline-3,3'-isochromane]-1',2-dione

[0110] The specific synthetic route is:

[0111] .

[0112] The specific preparation process is:

[0113] (1) Using N-methylindole and benzyl bromide as raw materials, 2-[(6-fluoro-1-methyl-1 H Synthesis of 2-[(1-benzyl-1-indol-3-yl)methyl]benzoic acid H -indol-3-yl)methyl]benzoic acid.

[0114] (2) Add 2-[(1-benzyl-1 H -indol-3-yl)methyl]benzoic acid (0.2 mmol, 71.3 mg), 2 mL of water, iodine (0.4 mmol, 101.6 mg), stirred at room temperature for 24 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 4:1).

[0115] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then the mixed solution was extracted with ethyl acetate (5 mL*4), the organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 4:1 volume ratio), and a colorless oily product was obtained, namely 1-allyl spiro[indoline-3,3'-isochromane]-1',2-dione, with a yield of 75%. Its nuclear magnetic resonance hydrogen spectrum is as follows Fig.14 As shown, the carbon NMR spectrum is Fig.15 The specific spectrum analysis data are as follows:

[0116] 1 H NMR (600 MHz, CDCl3) δ 8.21 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.5 Hz,1H), 7.50 (t, J = 7.6 Hz, 1H), 7.36 – 7.25 (m, 6H), 7.24 – 7.21 (m, 1H), 6.94 –6.85 (m, 2H), 6.75 (d, J = 7.9 Hz, 1H), 4.88 (s, 2H), 3.62 (d, J = 16.5 Hz, 1H),3.33 (d, J = 16.5 Hz, 1H).

[0117] 13C NMR (151 MHz, CDCl3) δ 172.6 (s), 163.8 (s), 142.4 (s), 135.9 (s), 135.0 (s), 134.39 (s), 131.0 (s), 130.2 (s), 129.0 (s), 128.4 (s), 128.2 (s), 128.0 (s), 127.4 (s), 125.0 (s), 124.2 (s), 123.4 (s), 110.1 (s), 80.6 (s), 44.1 (s), 34.4 (s).

[0118] Example 8: Preparation of 7'-chloro-1-methylspiro[indoline-3,3'-isochromane]-1',2-dione

[0119] The specific synthetic route is:

[0120] .

[0121] The specific preparation process is:

[0122] (1) Using N-methylindole and 5-chloro-2-formylbenzoic acid methyl ester as raw materials, 2-[(6-fluoro-1-methyl-1 H Synthesis of 5-chloro-2-[(1-methyl-1 H -indol-3-yl)methyl]benzoic acid.

[0123] (2) Add 5-chloro-2-[(1-methyl-1 H -indol-3-yl)methyl]benzoic acid (0.2 mmol, 59.8 mg), 2 mL of water, iodine (0.4 mmol, 101.6 mg), stirred at room temperature for 24 h, and the reaction progress was monitored by thin layer chromatography (volume ratio of petroleum ether to ethyl acetate = 4:1).

[0124] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then the mixed solution was extracted with ethyl acetate (5 mL*4), the organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 4:1 volume ratio), and a white solid product was obtained, namely 7'-chloro-1-methylspiro[indoline-3,3'-isochromane]-1',2-dione, with a yield of 70%. Its nuclear magnetic resonance hydrogen spectrum is as follows Fig.16 As shown, the carbon NMR spectrum is Fig.17 The specific spectrum analysis data are as follows:

[0125] 1 H NMR (600 MHz, CDCl3) δ 8.17 (d, J = 2.1 Hz, 1H), 7.56 (dd, J = 8.1, 2.2Hz, 1H), 7.41 – 7.37 (m, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.05 – 6.97 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 3.44 (d, J = 16.8 Hz, 1H), 3.34 (d, J = 16.8 Hz, 1H), 3.20 (s, 3H).

[0126] 13 C NMR (101 MHz, CDCl3) δ 172.3 (s), 162.8 (s), 143.4 (s), 134.4 (s), 134.3 (s), 134.2 (s), 131.4 (s), 130.0 (s), 129.5 (s), 127.0 (s), 126.5 (s), 124.2 (s), 123.6 (s), 109.1 (s), 80.5 (s), 33.8 (s), 26.6 (s).

[0127] Example 9: Scale-up experiment for the preparation of 1-methylspiro[indoline-3,3'-isochromane]-1',2-dione

[0128] The specific synthetic route is:

[0129] .

[0130] The specific preparation process is as follows: 2-[(1-methyl-1H-indol-3-yl)methyl]benzoic acid (4 mmol, 1.06 g), 40 mL of water and iodine (8 mmol, 2.032 g) are added sequentially into a round-bottom flask equipped with a magnetic rod, stirred at room temperature for 4 days, and the reaction progress is monitored by thin layer chromatography (the volume ratio of petroleum ether to ethyl acetate = 4:1).

[0131] After the reaction was completed, the reaction was quenched with a saturated Na2S2O3 solution, and then the mixed solution was extracted with ethyl acetate (30 mL*3), the organic phases were combined and dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the obtained crude product was purified and separated by column chromatography (column chromatography silica gel: 200-300 mesh; eluted with petroleum ether: ethyl acetate = 4:1 volume ratio) to obtain a white solid product with a yield of 81%. The characterization of hydrogen and carbon nuclear magnetic resonance spectra was the same as in Example 1.

[0132] Comparative Example 1

[0133] The difference from Example 1 is that the oxidizing agent iodine is replaced by an equal amount of NaIO4.

[0134] Comparative Example 2

[0135] The difference from Example 1 is that the oxidant iodine is replaced by an equal amount of NaIO3.

[0136] Comparative Example 3

[0137] The difference from Example 1 is that the oxidant iodine is replaced by 0.02 mmol NaI+0.6 mmol H2O2.

[0138] Comparative Example 4

[0139] The difference from Example 1 is that the oxidant iodine is replaced by 0.02 mmol TBAI+0.6 mmol H2O2.

[0140] Comparative Example 5

[0141] The difference from Example 1 is that the oxidant iodine is replaced by 0.02 mmol dodecyltrimethylammonium iodide+0.6 mmol H2O2.

[0142] Comparative Example 6

[0143] The difference from Example 1 is that the oxidant iodine is replaced by 0.02 mmol dodecyltrimethylammonium iodide + 0.6 mmol H2O2, and the reaction is heated at 60°C for 24 hours.

[0144] Comparative Example 7

[0145] The difference from Example 1 is that the solvent water is replaced by acetonitrile.

[0146] Comparative Example 8

[0147] The difference from Example 1 is that the solvent water is replaced by ethyl acetate.

[0148] Comparative Example 9

[0149] The difference from Example 1 is that the solvent water is replaced by dichloromethane.

[0150] Comparative Example 10

[0151] The difference from Example 1 is that the atmosphere is replaced with nitrogen.

[0152] The product yields of Comparative Examples 1 to 10 are shown in Table 1.

[0153] Table 1 Yield of each comparative example

[0154]

[0155] It can be seen from Table 1 that in Comparative Examples 1 to 6, the oxidant in the present invention is replaced by some common inorganic high-valent iodine reagents and iodine salt catalytic oxidation systems (including NaIO4, NaIO3, iodine salt + H2O2), and the product yield obtained is much lower than that in Example 1.

[0156] Comparative Examples 7 to 9 show the results of the reaction in some common organic solvents, but no better results were obtained than in the aqueous phase system, which may be attributed to the promotion of the reaction by the hydrophobic effect. In addition, Comparative Example 10 shows the experimental results under a nitrogen atmosphere, indicating that the yield of the product obtained is similar regardless of whether it is under an air atmosphere or a nitrogen atmosphere, confirming that the oxygen atoms in the product come from water rather than air.

[0157] The above description is only the preferred embodiment of the present application and is not intended to limit the present application. For those skilled in the art, the present application may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing an indole spiroisochromanone derivative, characterized in that: The preparation method is: An indole derivative containing an aromatic carboxylic acid is used as a substrate, iodine is used as an oxidant, and water is used as a solvent, and the reaction is stirred to obtain an indole spiroisochromanone derivative; The structural formula of the indole derivative containing aromatic carboxylic acid is: ； The structural formula of the indole spiroisochromanone derivative is: ； Among them, R 1 is hydrogen, fluorine, bromine, methyl or methoxy; R 2 is methyl, allyl or benzyl; R 3 is hydrogen or chlorine; The molar ratio of the substrate to the oxidant is 1:2; the added amount ratio of the substrate to the solvent is 1 mmol:10 mL.

2. The preparation method according to claim 1, characterized in that: The temperature of the stirring reaction is 20-40°C.

3. The preparation method according to claim 2, characterized in that: The temperature of the stirring reaction was 25°C.

4. The preparation method according to claim 1, characterized in that: The stirring reaction time is 4 to 96 hours.

5. The preparation method according to claim 4, characterized in that: The stirring reaction time is 24h.

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