An arylvinyl cyclic hypervalent iodine compound, a preparation method thereof and applications thereof

Abstract

The present invention belongs to the field of biomedical technology, and particularly relates to an arylvinyl cyclic hypervalent iodine compound, a preparation method thereof and an application thereof. The compound has a novel and stable structure, and has remarkable anti-tumor cell effects. In particular, the IC50 values for A549, DLD-1, and PANC-1 tumor cells are relatively low, and the anti-tumor cell effects are significant, showing good application prospects in anti-tumor treatment. Additionally, the preparation method of the arylvinyl cyclic hypervalent iodine compound is simple and feasible, and can be used for large-scale industrial production, providing more drug options for anti-tumor medical research and clinical applications.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine. More specifically, it relates to an arylvinyl cyclic hypervalent iodine compound, a preparation method thereof, and an application thereof. Background Art

[0002] A tumor refers to a local mass formed by abnormal proliferation of cells in local tissues under the action of various tumorigenic factors, and is mainly divided into benign tumors and malignant tumors. Among them, benign tumors are easy to be completely removed, generally do not metastasize or recur, and only have squeezing and obstructive effects on organs and tissues; while malignant tumors, in addition to squeezing and obstructive effects, also damage the structure and function of tissues and organs, cause necrosis, bleeding and combined infections, and patients may ultimately die due to organ failure. Cancers caused by malignant tumors seriously affect the lives and health of humans globally. Over the years, institutions in various countries have paid increasing attention to the research on cancer treatment and invested more and more, yet the number of cancer patients and the mortality rate remain high.

[0003] Currently, the main treatment methods for cancer include surgical treatment, chemotherapy, radiotherapy, targeted therapy, immunotherapy, traditional Chinese medicine treatment, gene therapy, endocrine therapy, hyperthermia treatment, laser treatment, cryotherapy, etc. Among them, chemotherapy is one of the most commonly used treatment methods. For example, Chinese Patent Application CN103172612A discloses a dibenzoiodonium salt, and these iodonium salts can significantly inhibit the growth of malignant tumor cells such as human pancreatic cancer, gastric cancer, and colorectal cancer in in vitro experiments, and have obvious killing effects on other malignant tumor cells such as ovarian cancer, lung cancer, liver cancer cells, leukemia, glioblastoma, and myeloma; they can also significantly inhibit the growth of human pancreatic cancer and colorectal cancer xenografts in animal experiments, and have significant anti-tumor effects. However, the currently available chemotherapy drugs are limited, and there is still a need to provide more anti-tumor drugs to provide more choices for medical research and clinical applications. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to overcome the defects and deficiencies of the limited existing anti-tumor drugs and provide an arylvinyl cyclic hypervalent iodine compound with significant anti-tumor effects.

[0005] The object of the present invention is to provide a preparation method of the arylvinyl cyclic hypervalent iodine compound.

[0006] Another object of the present invention is to provide the application of the arylvinyl cyclic hypervalent iodine compound in the preparation of anti-tumor drugs.

[0007] The above objects of the present invention are achieved by the following technical solutions:

[0008] An arylvinyl cyclic hypervalent iodine compound, the arylvinyl cyclic hypervalent iodine compound has a structure of formula (I):

[0009]

[0010] Among them, R is mono-substituted or multi-substituted, and is selected from hydrogen, halogen, cyano, C 1～6 alkyl, halo C 1～6 alkyl, C 1～6 alkoxy, halo C 1～6 alkoxy, C 3～6 cycloalkyl, phenyl, benzyl, naphthyl, or one or more of them.

[0011] Preferably, R is hydrogen, C 1～4 alkyl, halogen or benzyl.

[0012] Specifically, the present invention provides an arylvinyl cyclic hypervalent iodine compound, and the arylvinyl cyclic hypervalent iodine compound has any one of the following structures:

[0013]

[0014] In addition, the present invention also provides a preparation method of the arylvinyl cyclic hypervalent iodine compound, and the synthesis route is as follows:

[0015]

[0016] Specifically, it includes the following steps:

[0017] S1. Place compound (Ia) in an aprotic organic solvent, add iodine and an organic base reagent, react completely, and perform post-treatment to obtain compound (Ib);

[0018] S2. Place compound (Ib) in a polar organic solvent, add an oxidizing agent and an organic acid reagent (preferably trifluoromethanesulfonic acid), react completely, and perform post-treatment to obtain compound (I);

[0019] Among them, the definition of R is the same as above.

[0020] Furthermore, in steps S1 and S2, the reaction is carried out at room temperature. Preferably, in step S1, the reaction time is 12 to 24 hours; in step S2, the reaction time is 0.5 to 2 hours.

[0021] Even further, in step S1, the molar concentration ratio of compound (Ia), iodine, and the organic base reagent is 1:(1.05 - 2):(2 - 4); preferably, the molar concentration ratio of compound (Ia), iodine, and the organic base reagent is 1:1.05:2.

[0022] Preferably, in step S1, the specific operation of the post-treatment is as follows: after the reaction is completed, the reaction solution is extracted with ethyl acetate, and the combined ethyl acetate organic phase is washed 1-3 times each with saturated sodium thiosulfate and saturated brine; dried over anhydrous sodium sulfate, filtered, the solvent is removed under reduced pressure, and the obtained residue is eluted and purified by silica gel column chromatography (eluent petroleum ether:ethyl acetate = 100 / 1 - 50 / 1).

[0023] Furthermore, in step S2, the molar concentration ratio of the compound (Ib), the oxidant, and the organic acid reagent is 1:(1.2 - 2.5):(3 - 6); preferably, the molar concentration ratio of the compound (Ib), the oxidant, and the organic acid reagent is 1:1.5:3.

[0024] Preferably, in step S1, the aprotic organic solvent is a solution such as benzene, toluene, or diethyl ether.

[0025] Preferably, in step S1, the organic base reagent is morpholine, triethylamine, diisopropylethylamine, etc.

[0026] Preferably, in step S2, the polar organic solvent is dichloromethane, chloroform, acetonitrile, ethyl acetate, etc.

[0027] Preferably, in step S2, the oxidant is m-chloroperbenzoic acid, potassium permanganate, sodium periodate, etc.; more preferably m-chloroperbenzoic acid.

[0028] Preferably, in step S2, the specific operation of the post-treatment is as follows: after the reaction is completed, the solvent of the reaction solution is removed under reduced pressure, ether is added to the residue, mixed and stirred, filtered, and the solid is washed 1-5 times with ether.

[0029] In addition, the arylvinyl cyclic hypervalent iodine compound provided by the present invention has a significant inhibitory effect on tumor cells. Therefore, the present invention also claims the application of the arylvinyl cyclic hypervalent iodine compound in the preparation of anti-tumor drugs.

[0030] Furthermore, the tumor includes human non-small cell lung cancer tumor cells, human colorectal adenocarcinoma epithelial cells, or human pancreatic cancer tumor cells.

[0031] Even further, the drug further includes pharmaceutically acceptable excipients and is made into oral preparations, injection preparations, inhalation preparations, or external preparations.

[0032] The present invention has the following beneficial effects:

[0033] The present invention provides an arylvinyl cyclic hypervalent iodine compound, which has a novel and stable structure and remarkable anti-tumor cell effects. In particular, it has a low IC50 against A549, DLD-1, and PANC-1 tumor cells, and has significant anti-tumor cell effects, showing good application prospects in anti-tumor treatment. Additionally, the preparation method of the arylvinyl cyclic hypervalent iodine compound is simple and feasible, and can be mass-produced industrially, providing more drug options for anti-tumor medical research and clinical applications. Detailed implementation manners

[0034] The following specific examples are used to further illustrate the present invention, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in the technical field.

[0035] Unless otherwise specified, the reagents and materials used in the following examples are all commercially available.

[0036] Example 1 Preparation of Compound 1

[0037] The synthetic route of Compound 1 is as follows:

[0038]

[0039] Specifically, it includes the following steps:

[0040] S1. Preparation of Compound 1a: Add iodine (2.98 g, 11.75 mmol) and morpholine (1.71 mL, 19.58 mmol) to a benzene solution (20 mL) of phenylacetylene (1.0 g, 9.79 mmol), and react at room temperature for 24 hours. Monitor the reaction by TLC. After the reaction is completed, extract the reaction solution with ethyl acetate; wash the combined ethyl acetate organic phase with saturated sodium thiosulfate and saturated brine once each; dry with anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. The obtained residue is eluted and purified by silica gel column chromatography (eluent petroleum ether:ethyl acetate = 100 / 1 - 50 / 1) to obtain yellow solid Compound 1a (2.15 g, 96% yield).

[0041] S2. Preparation of Compound 1: Add m-chloroperbenzoic acid (1.34 g, 6.58 mmol, mass purity 85%) and trifluoromethanesulfonic acid (1.16 mL, 13.16 mmol) to a dichloromethane solution (44 mL) of Compound 1a (1.0 g, 4.39 mmol) obtained in Step S1 in batches and slowly, stir and react at room temperature for 1 hour, remove the solvent under reduced pressure, add ether (10 mL) to the residue, mix and stir for 20 minutes, filter, and wash the solid with ether 3 times to finally obtain white solid Compound 1 (1.43 g, 62% yield).

[0042] 1 1H NMR (400 MHz, DMSO) δ 8.37 (d, J = 8.1 Hz, 1H), 7.97 (t, J = 7.3 Hz, 1H), 7.86 (dd, J = 15.6, 7.3 Hz, 2H) ppm. 13 13C NMR (100 MHz, DMSO) δ 149.4, 134.5, 131.3, 130.8, 130.3, 125.9, 121.50, 113.6 ppm. 19 19F NMR (376 MHz, DMSO) δ -72.0, -72.7 ppm.

[0043] Preparation of Compound 2 in Example 2

[0044] The synthetic route of the said Compound 2 is as follows:

[0045]

[0046] Specifically, it includes the following steps:

[0047] S1. Preparation of Compound 2a: Add iodine (2.62 g, 10.33 mmol) and morpholine (1.51 mL, 17.22 mmol) to a benzene solution (20 mL) of p-methylphenylacetylene (1.0 g, 8.61 mmol), and carry out the reaction at room temperature for 24 hours. Detect the reaction situation by TLC. After the reaction is completed, extract the reaction solution with ethyl acetate; wash the combined ethyl acetate organic phase with saturated sodium thiosulfate and saturated brine once each; dry with anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. The obtained residue is eluted and purified by silica gel column chromatography (eluent petroleum ether:ethyl acetate = 100 / 1 - 50 / 1) to obtain yellow solid Compound 2a (1.93 g, 93% yield).

[0048] S2. Preparation of Compound 2: Slowly add m-chloroperbenzoic acid (1.26 g, 6.20 mmol, mass purity 85%) and trifluoromethanesulfonic acid (1.09 mL, 12.39 mmol) to a dichloromethane solution (42 mL) of the Compound 2a (1.0 g, 4.13 mmol) obtained in Step S2 in batches at room temperature, stir for 1 hour, remove the solvent under reduced pressure, add ether (10 mL) to the residue, stir the mixture for 20 minutes, filter, and wash the solid with ether 3 times to finally obtain white solid Compound 2 (1.54 g, 69% yield).

[0049] 11H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 8.14 (s, 1H), 7.77 (s, 2H), 2.52 (s, 3H) ppm. 13 13C NMR (100 MHz, DMSO) δ 149.8, 143.2, 132.0, 130.3, 126.2, 120.1, 108.0, 21.4 ppm. 19 19F NMR (376 MHz, DMSO) δ -72.4, -77.7 ppm.

[0050] Preparation of Compound 3 in Example 3

[0051] The synthetic route of the said Compound 3 is as follows:

[0052]

[0053] Specifically, it includes the following steps:

[0054] S1. Preparation of Compound 3a: To a benzene solution (20 mL) of p-fluorophenylacetylene (1.0 g, 8.32 mmol), iodine (2.54 g, 9.99 mmol) and morpholine (1.46 mL, 16.65 mmol) were added, and the reaction was carried out at room temperature for 24 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was extracted with ethyl acetate. The combined ethyl acetate organic phases were washed successively with saturated sodium thiosulfate and saturated brine once each; dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The obtained residue was eluted and purified by silica gel column chromatography (eluent petroleum ether:ethyl acetate = 100 / 1 - 50 / 1) to obtain colorless liquid Compound 3a (1.75 g, 85% yield).

[0055] S2. Preparation of Compound 3: To a dichloromethane solution (33 mL) of Compound 3a (800 mg, 3.25 mmol) obtained in Step S1, m-chloroperbenzoic acid (990 mg, 4.88 mmol, mass purity 85%) and trifluoromethanesulfonic acid (0.86 mL, 9.76 mmol) were added slowly in portions, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. Diethyl ether (10 mL) was added to the residue, and the mixture was stirred for 20 minutes, then filtered. The solid was washed 3 times with diethyl ether to finally obtain white solid Compound 3 (953 mg, 54% yield).

[0056] 1 1H NMR (500 MHz, DMSO) δ 8.77 (s, 1H), 8.16 (dd, J = 7.7, 2.4 Hz, 1H), 7.91 (dd, J = 8.8, 4.9 Hz, 1H), 7.86 (td, J = 8.6, 2.4 Hz, 1H). 1919F NMR (376 MHz, DMSO) δ -72.4, -78.0, -105.5 ppm.

[0057] Preparation of Compound 4 in Example 4

[0058] The synthetic route of the said Compound 4 is as follows:

[0059]

[0060] Specifically, it includes the following steps:

[0061] S1. Preparation of Compound 4a: To a benzene solution (20 mL) of p-chlorophenylacetylene (1.0 g, 7.32 mmol), iodine (2.23 g, 8.79 mmol) and morpholine (1.28 mL, 14.64 mmol) were added, and the reaction was carried out at room temperature for 24 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was extracted with ethyl acetate; the combined ethyl acetate organic phase was washed successively with saturated sodium thiosulfate and saturated brine once each; dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The obtained residue was eluted and purified by silica gel column chromatography (eluent petroleum ether:ethyl acetate = 100 / 1 - 50 / 1) to obtain yellow solid Compound 4a (1.74 g, 91% yield).

[0062] S2. Preparation of Compound 4: To a dichloromethane solution (38 mL) of Compound 4a (1.0 g, 3.81 mmol) obtained in Step S1, m-chloroperbenzoic acid (1.16 g, 5.71 mmol, mass purity 85%) and trifluoromethanesulfonic acid (1.01 mL, 11.43 mmol) were added slowly in batches, and the reaction was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. Ether (10 mL) was added to the residue, and the mixture was stirred for 20 minutes, filtered, and the solid was washed with ether 3 times. Finally, white solid Compound 4 (1.26 g, 59% yield) was obtained.

[0063] 1 1H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.34 (s, 1H), 8.03 (dd, J = 8.5, 1.9 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H). 13 13C NMR (100 MHz, DMSO) δ 149.0, 136.3, 133.6, 131.4, 129.9, 127.7, 121.3, 110.6 ppm. 19 19F NMR (376 MHz, DMSO) δ -72.4, -77.8 ppm.

[0064] Preparation of Compound 5 in Example 5

[0065] The synthetic route of Compound 5 is as follows:

[0066]

[0067] Specifically, it includes the following steps:

[0068] S1. Preparation of Compound 5a: Add iodine (1.68 g, 6.63 mmol), morpholine (0.97 mL, 11.05 mmol) to a benzene solution (15 mL) of p-bromophenylacetylene (1.0 g, 5.52 mmol), and carry out the reaction at room temperature for 24 hours. Monitor the reaction by TLC. After the reaction is completed, extract the reaction solution with ethyl acetate; wash the combined ethyl acetate organic phase with saturated sodium thiosulfate and saturated brine once each; dry with anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and purify the obtained residue by silica gel column chromatography (eluent petroleum ether:ethyl acetate = 100 / 1 - 50 / 1) to obtain yellow solid Compound 5a (1.36 g, 80% yield).

[0069] S2. Preparation of Compound 5: Slowly add m-chloroperoxybenzoic acid (0.7 g, 3.43 mmol, mass purity 85%) and trifluoromethanesulfonic acid (0.6 mL, 6.86 mmol) in batches to a dichloromethane solution (23 mL) of Compound 5a (600 mg, 2.29 mmol) obtained in Step S1, stir and react at room temperature for 1 hour, remove the solvent under reduced pressure, add ether (10 mL) to the residue, stir the mixture for 20 minutes, filter, and wash the solid with ether 3 times to finally obtain white solid Compound 5 (0.59 g, 46% yield).

[0070] 1 H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 8.47 (d, J = 1.7 Hz, 1H), 8.16 (dd, J = 8.4, 1.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H). 13 C NMR (100 MHz, DMSO) δ 149.2, 134.2, 133.9, 132.6, 127.9, 124.8, 121.5, 110.6 ppm. 19 F NMR (376 MHz, DMSO) δ -71.8, -72.4, -77.8 ppm.

[0071] Preparation of Compound 6 in Example 6

[0072] The synthetic route of Compound 6 is as follows:

[0073]

[0074] Specifically, it includes the following steps:

[0075] S1. Preparation of compound 6a: To a benzene solution (15 mL) of p-tert-butylphenylacetylene (1.0 g, 6.32 mmol), iodine (1.92 g, 7.58 mmol) and morpholine (1.11 mL, 12.64 mmol) were added, and the reaction was carried out at room temperature for 24 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction solution was extracted with ethyl acetate. The combined ethyl acetate organic phase was washed successively with saturated sodium thiosulfate and saturated brine once each. It was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The obtained residue was eluted and purified by silica gel column chromatography (eluent petroleum ether:ethyl acetate = 100 / 1 - 50 / 1) to obtain yellow solid compound 6a (1.54 g, 6% yield).

[0076] S2. Preparation of compound 6: To a dichloromethane solution (25 mL) of compound 6a (700 mg, 2.46 mmol) obtained in step S1, m-chloroperbenzoic acid (750 mg, 3.70 mmol, mass purity 85%) and trifluoromethanesulfonic acid (0.65 mL, 7.39 mmol) were added slowly in batches, and the reaction was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. Ether (10 mL) was added to the residue, and the mixture was stirred for 20 minutes, filtered, and the solid was washed with ether 3 times. Finally, white solid compound 6 (0.81 g, 56% yield) was obtained.

[0077] 1 H NMR (400 MHz, DMSO) δ 8.73 (s, 1H), 8.36 (d, J = 1.3 Hz, 1H), 8.03 (dd, J = 8.3, 1.3 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 1.37 (s, 9H). 13 C NMR (100 MHz, DMSO) δ 155.7, 149.7, 132.1, 128.6, 126.8, 126.2, 122.0, 120.6, 119.4, 116.8, 108.5, 35.7, 30.8 ppm. 19 F NMR (376 MHz, DMSO) δ -72.5, -77.8 ppm.

[0078] Preparation of compound 7 in Example 7

[0079] The synthetic route of the said compound 7 is as follows:

[0080]

[0081] Specifically, it includes the following steps:

[0082] S1. Preparation of Compound 7a: To a benzene solution (20 mL) of 2-fluorophenylacetylene (1.0 g, 8.32 mmol) was added iodine (2.54 g, 9.99 mmol) and morpholine (1.46 mL, 16.65 mmol), and the reaction was carried out at room temperature for 24 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was extracted with ethyl acetate. The combined ethyl acetate organic phase was washed successively with saturated sodium thiosulfate and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 100 / 1 - 50 / 1) to obtain yellow solid compound 7a (1.55 g, 76% yield).

[0083] S2. Preparation of Compound 7: To a dichloromethane solution (41 mL) of compound 7a (1.0 g, 4.06 mmol) obtained in step S1 was added m-chloroperoxybenzoic acid (1.24 g, 6.10 mmol, mass purity 85%) and trifluoromethanesulfonic acid (1.08 mL, 12.19 mmol) in batches slowly, and the reaction was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. Ether (10 mL) was added to the residue, and the mixture was stirred for 20 minutes, filtered, and the solid was washed with ether three times to finally obtain white solid compound 7 (1.22 g, 55% yield).

[0084] 1 H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 8.23 (dd, J = 11.5, 4.2 Hz, 1H), 7.91–7.75 (m, 2H) ppm.

[0085] Preparation of Compound 8 in Example 8

[0086] The synthetic route of the said compound 8 is as follows:

[0087]

[0088] Specifically, it includes the following steps:

[0089] S1. Preparation of Compound 8a: To a benzene solution (15 mL) of 2-naphthylacetylene (1.0 g, 6.57 mmol) was added iodine (2.0 g, 7.88 mmol) and morpholine (1.15 mL, 13.14 mmol), and the reaction was carried out at room temperature for 24 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was extracted with ethyl acetate. The combined ethyl acetate organic phase was washed successively with saturated sodium thiosulfate and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 100 / 1 - 50 / 1) to obtain yellow solid compound 8a (1.49 g, 82% yield).

[0090] S2. Preparation of Compound 8: To a dichloromethane solution (18 mL) of compound 8a (500 mg, 1.80 mmol) obtained in step S1 was added m-chloroperbenzoic acid (547 mg, 2.70 mmol, mass purity 85%) and trifluoromethanesulfonic acid (0.48 mL, 5.39 mmol) in portions slowly, and the reaction was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. To the residue was added diethyl ether (10 mL), and the mixture was stirred for 20 minutes, filtered, and the solid was washed with diethyl ether 3 times to finally obtain white solid compound 8 (0.52 g, 50% yield).

[0091] 1 H NMR (400 MHz, DMSO) δ 9.14 (s, 1H), 8.55 (d, J = 7.7 Hz, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.26 (d, J = 7.3 Hz, 1H), 7.89 (dt, J = 12.1, 5.9 Hz, 2H), 7.83 (d, J = 8.6 Hz, 1H) ppm. 13 C NMR (100 MHz, DMSO) δ 150.5, 134.3, 133.7, 132.1, 130.6, 129.9, 129.7, 129.3, 126.6, 125.0, 122.3, 122.0, 119.4, 116.9, 109.6 ppm. 19 F NMR (376 MHz, DMSO) δ -72.3, -77.8 ppm.

[0092] Preparation of Compound 9 in Example 9

[0093] The synthetic route of the said compound 9 is as follows:

[0094]

[0095] Specifically, it includes the following steps:

[0096] S1. Preparation of Compound 9a: To a benzene solution (15 mL) of 2-benzylphenylacetylene (1.0 g, 5.20 mmol) was added iodine (1.58 g, 6.24 mmol) and morpholine (0.91 mL, 10.40 mmol). The reaction was carried out at room temperature for 24 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was extracted with ethyl acetate. The combined ethyl acetate organic phases were washed successively with saturated sodium thiosulfate and saturated brine once each, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue obtained was eluted and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 100 / 1 - 50 / 1) to obtain yellow solid compound 9a (1.27 g, 77% yield).

[0097] S2. Preparation of Compound 9: To a dichloromethane solution (16 mL) of compound 9a (500 mg, 1.57 mmol) obtained in step S1 was added m-chloroperbenzoic acid (0.48 g, 2.36 mmol, mass purity 85%) and trifluoromethanesulfonic acid (0.42 mL, 4.71 mmol) in batches and slowly. The reaction was stirred at room temperature for 1 hour, and the solvent was removed under reduced pressure. Ether (10 mL) was added to the residue, and the mixture was stirred for 20 minutes, filtered, and the solid was washed with ether 3 times. Finally, white solid compound 9 (0.45 g, 46% yield) was obtained.

[0098] 1 H NMR (400 MHz, DMSO) δ 8.20 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.84 (t, J = 9.6 Hz, 1H), 7.73–7.67 (m, 3H), 7.61 (t, J = 8.0 Hz, 2H), 7.51–7.46 (m, 1H), 4.39–4.22 (m, 2H) ppm.

[0099] Application Example 1 Tumor Activity Effect of Arylethenylcyclic Hypervalent Iodine Compounds

[0100] 1. Experimental Method

[0101] The killing effect of drug molecules on tumor cells was determined by the in vitro MTT method: Human tumor cells in the logarithmic growth phase, namely human non-small cell lung cancer cells (A549), human colorectal adenocarcinoma epithelial cells (DLD-1), and human pancreatic cancer tumor cells (PANC-1), were digested, centrifuged, and counted to make the cell density at 3×10 4About 3000 cells were seeded in a 96-well plate, i.e., 3000 cells were seeded in each well. After the cells adhered, a culture medium containing arylvinyl cyclic hypervalent iodine compounds at different concentrations was added (three replicate wells were set for each drug concentration, and a blank well was set for zero adjustment. The DMSO concentration in the arylvinyl cyclic hypervalent iodine compound solution was controlled within 0.1%). After incubation in a carbon dioxide incubator for 72 hours, 5 mg / ml of MTT was added. After 4 hours, 200 μl of DMSO was added to dissolve the purple formazan (the number of live cells is proportional to the production of formazan). After shaking on a room temperature shaker for 10 minutes, the absorbance value of the 96-well plate at a wavelength of 570 nm was measured using an enzyme-linked immunosorbent assay (ELISA) reader. The experiment was repeated three times.

[0102] The formula for calculating cell viability is: average absorbance value of the drug treatment group / average absorbance value of the control group × 100%. The IC50 is the drug concentration at which 50% of the tumor cells die due to the arylvinyl cyclic hypervalent iodine compound. A cell survival curve was plotted using Prism software and the IC50 value was calculated. The results are shown in Table 1.

[0103] 2. Experimental Results

[0104] Table 1 IC50 of arylvinyl cyclic hypervalent iodine compounds against human tumor cells

[0105]

[0106] As can be seen from the table, the arylvinyl cyclic hypervalent iodine compounds of the present invention have significant inhibitory effects on human non-small cell lung cancer cells (A549), human colorectal adenocarcinoma epithelial cells (DLD-1), and human pancreatic cancer tumor cells (PANC-1), and have good anti-tumor activity.

[0107] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and shall be included in the protection scope of the present invention.

Claims

1. An arylvinyl cyclic hypervalent iodine compound, characterized in that, The arylvinyl cyclic hypervalent iodine compound has the structure of formula (I): Among them, R is mono-substituted or multi-substituted and is selected from hydrogen, halogen, cyano, C 1～6 alkyl, halo-C 1～6 alkyl, C 1～6 alkoxy, halo-C 1～6 alkoxy, C 3～6 cycloalkyl, phenyl, benzyl, naphthyl, or one or more thereof.

2. The arylvinyl cyclic hypervalent iodine compound according to claim 1, wherein R is hydrogen, C 1～4 alkyl, halogen or benzyl.

3. An arylvinyl cyclic hypervalent iodine compound, characterized in that, The arylvinyl cyclic hypervalent iodine compound has any of the following structures:

4. The preparation method of the arylvinyl cyclic hypervalent iodine compound according to any one of claims 1 to 3, characterized in that, The synthetic route is as follows: Specifically, it includes the following steps: S1. Place the compound (Ia) in an aprotic organic solvent, add iodine and an organic base reagent, react completely, and perform post-treatment to obtain the compound (Ib); S2. Place the compound (Ib) in a polar organic solvent, add an oxidant and an organic acid reagent, react completely, and perform post-treatment to obtain the compound (I); Among them, the definition of R is the same as any one of claims 1 to 3.

5. The preparation method according to claim 4, characterized in that, In steps S1 and S2, the reaction is carried out at room temperature.

6. According to the preparation method described in claim 4, characterized in that, In step S1, the molar concentration ratio of the compound (Ia), iodine, and the organic base reagent is 1:(1.05 - 2):(2 - 4).

7. According to the preparation method described in claim 4, characterized in that, In step S2, the molar concentration ratio of the compound (Ib), the oxidant, and the organic acid reagent is 1:(1.2 - 2.5):(3 - 6).

8. Use of the arylvinyl cyclic hypervalent iodine compound according to any one of claims 1 to 3 in the preparation of an anti-tumor drug.

9. The application according to claim 8, characterized in that, The tumor includes human non-small cell lung cancer tumor cells, human colorectal adenocarcinoma epithelial cells, or human pancreatic cancer tumor cells.

10. The application according to claim 9, wherein The drug further includes pharmaceutically acceptable excipients and is made into an oral preparation, an injection, an inhalant, or a topical preparation.

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