3-amino-2-indolinone compound containing a sulfur acetal skeleton, and a synthesis method and application thereof

Abstract

This invention belongs to the field of organic chemical synthesis, specifically relating to a 3-amino-2-indolone compound containing a thioacetal skeleton, its synthesis method, and its applications. The synthesis method involves adding aryl-substituted dithioacetal and 1-substituted-3-imino-2-indolone as reactants to an organic solvent. The reaction is carried out under the synergistic catalysis of naphthol phosphate and a Cu metal catalyst at 2-5°C with stirring. The reaction is monitored by TLC until complete, followed by filtration, concentration, and purification to obtain the final product. The 3-amino-2-indolone compound synthesized in this invention possesses potential pharmaceutical activity due to its thioacetal skeleton. The reaction conditions of this invention are relatively conventional, the reaction process is mild, simple, and low-cost, suitable for large-scale industrial production, thus broadening the applicability of this method. A wide variety of substrates are used as reactants, resulting in structurally diverse products with high yields.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis, specifically relating to a 3-amino-2-indole ketone compound containing a thioacetal skeleton, its synthesis method, and its application. Background Technology

[0002] Sulfur-containing indole ketones are widely found in anticancer drug molecules and natural products, and have broad application prospects in the life sciences. For example, a spirocyclic indole ketone compound disclosed in Chinese patent literature (application number 201510834547.6) has a significant killing effect on human cancer cells, especially human breast cancer cell line MDA-MB-231, human cervical cancer cell line HeLa, or human lung cancer cell line A549. However, the preparation method of this compound is relatively complicated. For example, Chinese patent document (application number 201310540828.1) discloses a class of 1,3-substituted-5-acetamidoindolone compounds, including 1-methyl-5-acetamidoindolone, 1-(4-bromobenzyl)-5-acetamidoindolone, 1-(4-methylbenzyl)-3-oxime-5-acetamidoindolone, and 1-(4-methoxybenzyl)-3-oxime-5-acetamidoindolone. These compounds have a certain inhibitory effect (IC50) on human leukemia cells (K562), human colon cancer cells (HT-29), and human liver cancer cells (HepG2). 50 <100μM), but this does not include inhibition of HeLa and MDA-MB-231 tumor cells. Summary of the Invention

[0003] Research has shown that combining indole with a thioacetal skeleton is expected to have good antitumor activity. However, currently, indole ketones containing a thioacetal skeleton are a class of compounds that have never been studied, and no synthetic methods for these compounds have been investigated. Therefore, one of the objectives of this invention is to provide a 3-amino-2-indole ketone compound containing a thioacetal skeleton, thereby expanding the range of indole ketones and thioacetals.

[0004] The second objective of this invention is to provide a method for synthesizing the above-mentioned 3-amino-2-indolone compounds containing a thioacetal skeleton. This method is mild, simple, safe and easy to operate, and has the advantages of low cost and high yield.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is: a 3-amino-2-indolone compound containing a thioacetal skeleton, the chemical structural formula of which is shown in Formula 3:

[0006] ;

[0007] In Formula 3, Ar is selected from one of 2-naphthyl, phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, fluorine-substituted phenyl, chlorine-substituted phenyl, and bromine-substituted phenyl; R 1 Selected from one of methyl, acetyl, benzyl, and allyl; R 2 It is selected from one of halogen-substituted phenyl, methyl-substituted phenyl, and nitro-substituted phenyl.

[0008] The present invention also provides a method for synthesizing the above-mentioned 3-amino-2-indolone compounds containing a thioacetal skeleton. The specific steps are as follows: aryl-substituted dithioacetal of Formula 1 and 1-substituted-3-imino-2-indolone of Formula 2 are added to an organic solvent as reactants. The reaction is stirred under the synergistic catalysis of naphthol phosphate and Cu metal catalyst at 2-5 °C. The reaction is monitored by TLC until complete. The mixture is then filtered, concentrated, and purified to obtain the compound of Formula 3.

[0009] The molar ratio between compound aryl-substituted dithioacetal of formula 1 and compound 1-substituted-3-imino-2-indolone of formula 2 is 1:1, and the molar ratio between compound aryl-substituted dithioacetal of formula 1, naphthol phosphate, and Cu metal catalyst is 1:0.1:0.2.

[0010] The structural formula of the aryl-substituted dithioacetal of Formula 1 is as follows: In Formula 1, Ar is selected from one of 2-naphthyl, phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, fluorine-substituted phenyl, chlorine-substituted phenyl, and bromine-substituted phenyl.

[0011] The structural formula of compound 1-substituted-3-imino-2-indolone of formula 2 is as follows: In Equation 2, R 1 Selected from one of methyl, acetyl, benzyl, and allyl; R 2 It is selected from one of halogen-substituted phenyl, methyl-substituted phenyl, and nitro-substituted phenyl.

[0012] Preferably, the Cu metal catalyst is selected from monovalent copper catalysts and divalent copper catalysts; the monovalent copper catalyst is compound tetraacetonitrile tetrafluoroborate Cu(CH3CN)4BF4 (Formula 5), ​​compound tetraacetonitrile tetrafluorophosphate Cu(CH3CN)4PF6 (Formula 6), and compound cuprous iodide CuI (Formula 7), wherein the structural formula of compound 5 is [structural formula missing]. The structural formula of compound 6 is as follows: The structural formula of the compound of formula 7 is as follows: The divalent copper catalyst is compound Cu(OTf)2 trifluoromethanesulfonate, which is of formula 8. The structural formula of compound 8 is as follows: Preferably, the copper metal catalyst is copper tetrafluoroborate tetraacetonitrile Cu(CH3CN)4BF, a compound of formula 5. 4。

[0013] Preferably, the organic solvent is selected from ethyl acetate, toluene, methyl tert-butyl ether, and dichloromethane; the volume ratio of the organic solvent to the molar amount of methyl-substituted 2-indole methanol of Formula 1 is (5-10 mL): 1 mmol.

[0014] Preferably, the organic solvent is ethyl acetate, and the volume ratio of the organic solvent to the molar amount of the aryl-substituted dithioacetal of Formula 1 is 10 mL: 1 mmol.

[0015] Preferably, the molar ratio between the aryl-substituted dithioacetal of Formula 1 and the 1-substituted-3-imino-2-indolone of Formula 2 is 1:1.

[0016] Preferably, the reaction temperature is 5°C.

[0017] Preferably, the purification is performed by silica gel column chromatography, and the eluent is a mixture of petroleum ether and dichloromethane at a volume ratio of 5:1.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] (1) The 3-amino-2-indole ketone compounds with a thioacetal skeleton synthesized in this invention have common active functional groups such as thioacetal and amino groups, and have potential drug bioactivity. This indicates that the 3-amino-2-indole ketone compounds with a thioacetal skeleton synthesized in this invention are expected to be applied in the pharmaceutical field;

[0020] (2) The reaction conditions for synthesizing 3-amino-2-indolone compounds with a thioacetal skeleton are relatively conventional. The reaction process is mild, simple, easy to operate, and low in cost, making it suitable for large-scale industrial production and broadening the scope of application of this method. The present invention uses a variety of substrates as reactants to obtain products with diverse and complex structures and high yields. Detailed Implementation

[0021] In the examples below, unless otherwise stated, aryl-substituted dithioacetals, 1-substituted-3-imino-2-indolone, copper tetrafluoroborate tetraacetonitrile, naphthol phosphate, and other reagents are commercially available or obtained in accordance with known literature; the experimental methods described are generally performed under conventional conditions or conditions recommended by the manufacturer.

[0022] Example 1

[0023] The synthetic route for 3-amino-2-indolone compounds containing a thioacetal skeleton, formula 3a, is as follows:

[0024]

[0025] 0.1 mmol of phenyl-substituted dithioacetal (Formula 1a) and 0.1 mmol of 1-substituted-3-imino-2-indolone (Formula 2a) were added to a solvent as reactants. The reaction was carried out at 5 °C with stirring for 2 h under the action of 0.01 mmol of naphthol phosphate and 0.02 mmol of copper metal catalyst (Formula 5, 6, 7, or 8). The reaction was monitored by TLC until completion. After filtration and concentration, the product was purified by silica gel column chromatography (eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1) to obtain 3-amino-2-indolone compound (Formula 3a) with a thioacetal skeleton. The yields are shown in Table 1.

[0026] Table 1. Effects of different types of copper metal catalysts, solvents, temperatures, and stoichiometry on yield. a

[0027]

[0028] Note: The optimal reaction conditions can be obtained from the data in Table 1 as follows: copper metal catalyst is Formula 5, solvent is ethyl acetate, the volume of organic solvent is 1.0 mL, the reaction temperature is 5 ℃, and the equivalent ratio of Formula 1a: Formula 2a is 1:1.

[0029] The structural characterization data of product formula 3a obtained under the optimal reaction conditions in Example 1 are as follows:

[0030] 85% yield (47.4 mg) as a white solid. mp 118.3 – 119.5 o C; 1 H NMR(600 MHz, DMSO-d6) (δ, ppm) 7.94 (s, 1H), 7.81 (d, J = 12.0 Hz, 2H), 7.52 –7.47 (m, 1H), 7.44 (d, J = 12.0 Hz, 2H), 7.37 - 7.35 (comp, 2H), 7.27-7.24(comp, 2H), 7.20-7.18 (comp, 2H), 6.95-6.92 (m, 1H), 6.64-6.61 (m, 1H), 6.47(d, J = 6.0 Hz, 1H), 4.76-4.67 (m, 2H), 3.42-3.39 (m, 1H), 3.26 – 3.19 (m,2H), 3.12 – 3.09 (m, 1H), 1.21 (s, 9H).13 C NMR (150 MHz, DMSO-d6) (δ, ppm)195.0, 154.6, 143.9, 137.1, 136.7, 133.7, 130.7, 130.2, 129.2, 129.0, 128.8,127.8, 127.6, 124.4, 122.2, 122.1, 109.0, 79.3, 64.0, 43.8, 39.0, 37.8, 28.5;HRMS (TOF MS ESI + m / z: [M+H] + Calculated for C 31 H 31 N2O4S2 559.1720; found559.1723.

[0031] Example 2-11

[0032] The synthesis methods of Examples 2-11 are the same as those of Example 1, except that 1-substituted-3-imino-2-indolone with different structures are used as raw materials.

[0033] The reaction synthesis route is shown below:

[0034]

[0035] The products and yields are shown in Table 2 below:

[0036] Table 2. Reactants, products, and yields of Examples 1 and 2-11

[0037]

[0038] Examples 12-22

[0039] The synthesis methods of Examples 12-22 are the same as those of Example 1, except that different dithioacetals are used as raw materials.

[0040] The reaction synthesis route is shown below:

[0041]

[0042] The product yields are shown in Table 3 below:

[0043] Table 3. Reactants, products, and yields of Examples 12-22

[0044]

[0045] As shown in Tables 2 and 3, the method of the present invention can not only achieve the synthesis of 3-amino-2-indolone compounds with a sulfur acetal skeleton in one step, obtain excellent yield, high atom economy, environmental friendliness, and wide applicability, but also has readily available raw materials, simple and safe operation, mild reaction conditions, short reaction time, simple post-processing, and diversified product structure. Therefore, it has great implementation value and potential social and economic benefits.

[0046] Application testing, see Table 4:

[0047] Table 4 Application Test Results

[0048]

[0049] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the technical scope disclosed in the present invention, based on the technical solution and concept of the present invention, should be covered within the scope of protection of the present invention. It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present invention can be combined with each other.

Claims

1. A 3-amino-2-indolone compound containing a thioacetal skeleton, characterized in that, Its chemical structural formula is shown in Formula 3: ； In Formula 3, Ar is selected from one of 2-naphthyl, phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, fluorine-substituted phenyl, chlorine-substituted phenyl, and bromine-substituted phenyl; R 1 Selected from one of methyl, acetyl, benzyl, and allyl; R 2 It is selected from one of halogen-substituted phenyl, methyl-substituted phenyl, and nitro-substituted phenyl.

2. A method for synthesizing a 3-amino-2-indolone compound with a thioacetal skeleton as described in claim 1, characterized in that, The process includes the following steps: aryl-substituted dithioacetal of Formula 1 and 1-substituted-3-imino-2-indolone of Formula 2 are added to an organic solvent as reactants. The reaction is carried out under the synergistic catalysis of naphthol phosphate of Formula 4 and Cu metal catalyst at 2-5 °C. After the reaction is completed, the mixture is filtered, concentrated, and purified to obtain compound of Formula 3. The molar ratio between the aryl-substituted dithioacetal of Formula 1 and the 1-substituted-3-imino-2-indolone of Formula 2 is 1:1, and the molar ratio between the aryl-substituted dithioacetal of Formula 1 and the naphthol phosphate and Cu catalyst is 1:0.1:0.

2. The structural formula of the aryl-substituted dithioacetal of Formula 1 is as follows: In Formula 1, Ar is selected from one of 2-naphthyl, phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, fluorine-substituted phenyl, chlorine-substituted phenyl, and bromine-substituted phenyl. The structural formula of compound 1-substituted-3-imino-2-indolone of formula 2 is as follows: In Equation 2, R 1 Selected from one of methyl, acetyl, benzyl, and allyl; R 2 It is selected from one of halogen-substituted phenyl, methyl-substituted phenyl, and nitro-substituted phenyl; The structural formula of the 4-naphthol phosphate is as follows: .

3. The method for synthesizing 3-amino-2-indolone compounds with a thioacetal skeleton according to claim 2, characterized in that, The Cu metal catalyst is selected from compounds of formula 5 (copper tetrafluoroborate tetraacetonitrile Cu(CH3CN)4BF4), formula 6 (copper tetrafluorophosphate tetraacetonitrile Cu(CH3CN)4PF6), formula 7 (cuprous iodide CuI), and formula 8 (copper trifluoromethanesulfonate Cu(OTf)2). The structural formula of compound of formula 5 is as follows: The structural formula of compound 6 is as follows: The structural formula of the compound of formula 7 is as follows: The structural formula of compound 8 is as follows: .

4. The method for synthesizing 3-amino-2-indolone compounds with a thioacetal skeleton according to claim 3, characterized in that, The Cu metal catalyst is copper tetrafluoroborate tetraacetonitrile Cu(CH3CN)4BF4, and the molar ratio of the Cu metal catalyst to the aryl-substituted dithioacetal of Formula 1 is 0.2:

1.

5. The method for synthesizing 3-amino-2-indolone compounds with a thioacetal skeleton according to claim 2, characterized in that, The organic solvent is selected from ethyl acetate, toluene, methyl tert-butyl ether, and dichloromethane; the volume ratio of the organic solvent to the molar amount of the aryl-substituted dithioacetal of Formula 1 is (5-10 mL): 1 mmol.

6. The method for synthesizing 3-amino-2-indolone compounds with a thioacetal skeleton according to claim 2, characterized in that, The organic solvent is ethyl acetate, and the volume ratio of the organic solvent to the molar amount of the aryl-substituted dithioacetal of Formula 1 is 10 mL: 1 mmol.

7. The method for synthesizing 3-amino-2-indolone compounds with a thioacetal skeleton according to claim 2, characterized in that, The molar ratio between the aryl-substituted dithioacetal of Formula 1 and the 1-substituted-3-imino-2-indolone of Formula 2 is 1:

1.

8. The method for synthesizing 3-amino-2-indolone compounds with a thioacetal skeleton according to claim 2, characterized in that, The reaction temperature is 5℃.

9. The method for synthesizing 3-amino-2-indolone compounds with a thioacetal skeleton according to claim 2, characterized in that, The purification method was silica gel column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate at a volume ratio of 5:

1.

10. The application of the 3-amino-2-indolone compound with a thioacetal skeleton as described in claim 1, characterized in that, Application in the preparation of drugs that inhibit the growth of HeLa and MDA-MB-231 tumor cells.

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