Aryl ether compound as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicines, relates to an aryl ether compound as well as a preparation method and application thereof, and in particular relates to an aryl ether compound as well as a preparation method and application thereof in preparation of antibacterial and anti-tumor medicines. The structure of the aryl ether compound is as shown in general formulas I-IV, and in the general formulas I-IV, R1-R31 and n are as described in the claims and the description. The invention also provides a composition of the aryl ether compound or the pharmaceutically acceptable salt of the aryl ether compound. The compound or the composition thereof has obvious antibacterial and anti-tumor activity, and can be used for preparing antibacterial drugs or anti-tumor drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to aryl ether compounds, their preparation methods, and applications, particularly to aryl ether compounds, their preparation methods, and their applications in the preparation of antibacterial and antitumor drugs. Background Technology

[0002] Aryl ether compounds are mainly derived from the marine fungus Spiromastix sp. (MCCC 3A00308), which is mainly distributed in sedimentary rocks at depths of over 2,869 kilometers in the South Atlantic, making collection relatively difficult.

[0003] Currently, aryl ether compounds are found in low abundance in nature (some compounds are present in fermentation broth at concentrations below 0.5 mg / L). The number of aryl ether compounds discovered is limited, and no methods for their total synthetic preparation have been reported. There is no universal method for synthesizing compounds with various substitution conditions. Furthermore, there are no reports of the application of derivatives of this structure in the preparation of antibacterial or antitumor drugs. Summary of the Invention

[0004] The technical problem solved by this invention is to overcome the defects of the prior art and provide a series of new aryl ether compounds, which have significant antibacterial and antitumor activities.

[0005] This invention is achieved through the following techniques:

[0006] This invention provides aryl ether compounds of general formulas I-IV, or pharmaceutically acceptable salts thereof:

[0007]

[0008] in,

[0009] R1 can be a halogen, OH, trifluoromethanesulfonic acid group, cyano, benzyloxy, C1-C6 alkyl, C1-C6 alkoxy, or C2-C6 alkenyl.

[0010] R2 can be H, halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0011] R3 can be H, benzyl, C1-C6 alkyl, or C1-C6 alkoxy.

[0012] R4 can be H, halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0013] R5 is H, a halogen.

[0014] R6 is a C1-C6 alkyl or C1-C6 alkoxy group.

[0015] R7 can be H, halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0016] R8 can be OH, trifluoromethanesulfonic acid, C2-C6 alkenyl, benzyloxy, C1-C6 alkyl, or C1-C6 alkoxy.

[0017] R9 can be H, OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, or phenoxy.

[0018] R 10 It can be H, benzyl, C1-C6 alkyl, or C1-C6 alkoxy.

[0019] R 11 It can be H, halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0020] R 12 It can be H, benzyl, tert-butyldimethylsilyl, C1-C6 alkyl, or C1-C6 alkoxy.

[0021] R 13 It consists of H and halogens.

[0022] R 14 It can be H, benzyl, C1-C6 alkyl, or C1-C6 alkoxy.

[0023] R 15 It can be H, halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0024] n is 0-10, preferably 0-5, and more preferably 0-2.

[0025]

[0026] R 16 It can be halogen, OH, benzyloxy, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 alkenyl.

[0027] R 17 It can be H, halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0028] R 18 It can be H, benzyl, C1-C6 alkyl, or C1-C6 alkoxy.

[0029] R 19 It can be H, halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0030] R 20 It can be H, halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0031] R 21It can be H, halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0032] R 22 It can be H, benzyl, tert-butyldimethylsilyl, C1-C6 alkyl, or C1-C6 alkoxy.

[0033] R 23 It can be H, halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0034] R 24 It can be halogen, OH, amino, cyano, benzyloxy, phenoxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, or methyl methylene ether.

[0035] R 25 It can be H, OH, benzyl, C1-C6 alkyl, or C1-C6 alkoxy.

[0036]

[0037] R 26 It can be H, OH, halogen, benzyloxy, C1-C6 alkyl, or C1-C6 alkoxy.

[0038] R 27 It can be H, halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0039] R 28 It can be H, CH2OCH3, C1-C6 alkyl, benzyl, or C1-C6 alkoxy.

[0040] R 29 It can be H, halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0041] R 30 It can be H, halogen, OH, methyl methylene ether, benzyloxy, C1-C6 alkyl, C1-C6 alkoxy, or dimethyl tert-butyl silyl ether.

[0042] R 31 The values ​​are H, COR (R = H, OH, C1-C6 alkoxy, benzyloxy), OH, halogen, amino, cyano, benzyloxy, phenoxy, C1-C6 alkyl, C1-C6 alkoxy, and C2-C6 alkenyl.

[0043] The present invention preferably uses the following aryl ether compounds or pharmaceutically acceptable salts thereof:

[0044] R1 can be a halogen, OH, trifluoromethanesulfonic acid group, cyano, benzyloxy, C1-C4 alkyl, C1-C4 alkoxy, or C2-C4 alkenyl.

[0045] R2 can be H, Cl, C1-C4 alkyl, or C1-C4 alkoxy.

[0046] R3 can be H, benzyl, C1-C4 alkyl, or C1-C4 alkoxy.

[0047] R4 can be H, Cl, C1-C4 alkyl, or C1-C4 alkoxy.

[0048] R5 represents H and Cl.

[0049] R6 is a C1-C4 alkyl or C1-C4 alkoxy group.

[0050] R7 can be H, Cl, C1-C4 alkyl, or C1-C4 alkoxy.

[0051] R8 can be OH, trifluoromethanesulfonic acid group, C2-C4 alkenyl group, benzyloxy group, C1-C4 alkyl group, or C1-C4 alkoxy group.

[0052] R9 can be H, OH, halogen, C1-C4 alkyl, C1-C4 alkoxy, benzyloxy, or phenoxy.

[0053] R 10 It can be H, benzyl, C1-C4 alkyl, or C1-C4 alkoxy.

[0054] R 11 It can be H, halogen, C1-C4 alkyl, or C1-C4 alkoxy.

[0055] R 12 It can be H, benzyl, tert-butyldimethylsilyl, C1-C4 alkyl, or C1-C4 alkoxy.

[0056] R 13 It consists of H and halogens.

[0057] R 14 It can be H, benzyl, C1-C4 alkyl, or C1-C4 alkoxy.

[0058] R 15 It can be H, halogen, C1-C4 alkyl, or C1-C4 alkoxy.

[0059] n is 0-10, preferably 0-5, and more preferably 0-2.

[0060] R 16 It can be halogen, OH, benzyloxy, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 alkenyl.

[0061] R 17 It can be H, halogen, C1-C4 alkyl, or C1-C4 alkoxy.

[0062] R 18 It can be H, benzyl, C1-C4 alkyl, or C1-C4 alkoxy.

[0063] R 19 It can be H, halogen, C1-C4 alkyl, or C1-C4 alkoxy.

[0064] R 20 It can be H, halogen, C1-C4 alkyl, or C1-C4 alkoxy.

[0065] R 21 It can be H, halogen, C1-C4 alkyl, or C1-C4 alkoxy.

[0066] R 22 It can be H, benzyl, tert-butyldimethylsilyl, C1-C4 alkyl, or C1-C4 alkoxy.

[0067] R 23 It can be H, halogen, C1-C4 alkyl, or C1-C4 alkoxy.

[0068] R 24 It can be halogen, OH, amino, cyano, benzyloxy, phenoxy, C1-C4 alkyl, C1-C4 alkoxy, C2-C6 alkenyl, or methyl methylene ether.

[0069] R 25 It can be H, OH, benzyl, C1-C4 alkyl, or C1-C4 alkoxy.

[0070] R 26 It can be H, OH, F, benzyloxy, C1-C4 alkyl, or C1-C4 alkoxy.

[0071] R 27 It can be H, Cl, C1-C4 alkyl, or C1-C4 alkoxy.

[0072] R 28 It can be H, CH2OCH3, C1-C4 alkyl, benzyl, or C1-C4 alkoxy.

[0073] R 29 It can be H, Cl, C1-C4 alkyl, or C1-C4 alkoxy.

[0074] R 30 It can be H, F, I, OH, methyl methylene ether, benzyloxy, C1-C4 alkyl, C1-C4 alkoxy, or dimethyl tert-butyl silyl ether.

[0075] R 31 The values ​​are H, COR (R = H, OH, C1-C4 alkoxy, benzyloxy), OH, halogen, amino, cyano, benzyloxy, phenoxy, C1-C4 alkyl, C1-C4 alkoxy, and C2-C6 alkenyl.

[0076] The present invention preferably uses the following aryl ether compounds or pharmaceutically acceptable salts thereof:

[0077]

[0078]

[0079] The present invention also provides the following intermediates for preparing the aryl ether compounds or pharmaceutically acceptable salts thereof:

[0080]

[0081] Furthermore, the present invention provides a method for preparing aryl ether compounds represented by general formulas I-IV, comprising the following steps:

[0082] Aromatic compounds containing carboxylic acids and aromatic compounds containing alcohols are used to prepare compounds of general formula II by the action of dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP).

[0083] Compounds of general formula II first undergo deprotection reaction, and then undergo cyclization under the catalysis of copper or palladium salts to form compounds with a seven-membered lactone ring. Further modification and derivatization of the seven-membered lactone ring compound yields compounds of general formula I.

[0084] Compounds of general formula III are prepared by reacting aryl halides with phenolic compounds under the catalysis of copper or palladium salts.

[0085] Compound IV was prepared by reacting phenolic compounds with haloalkanes under the action of an alkali.

[0086] Preparation process of compounds of general formula II:

[0087]

[0088] Preparation process of compounds of general formula I:

[0089]

[0090] Preparation process of compounds of general formula III:

[0091]

[0092] Preparation process of compounds of general formula IV:

[0093]

[0094] Among them, R1-R 31 As mentioned before, n.

[0095] The present invention provides a pharmaceutical composition comprising an aryl ether compound of formula I-IV or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0096] The present invention further provides the use of aryl ether compounds of general formulas I-IV or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in the preparation of antibacterial or antitumor drugs.

[0097] The antibacterial drug mentioned is an antibacterial drug or an antifungal drug.

[0098] The bacteria mentioned are Escherichia coli, methicillin-resistant Staphylococcus aureus, etc.

[0099] The fungi mentioned are Candida albicans, Cryptococcus neoformans, etc.

[0100] The tumor in question is lung cancer.

[0101] The present invention also provides the use of the intermediate in the preparation of aryl ether compounds or pharmaceutically acceptable salts thereof. Detailed Implementation

[0102] The present invention will be further illustrated below with reference to specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in this technical field.

[0103] The reagents and instruments used in this embodiment are as follows:

[0104] Reagents: 2,6-difluoro-4-hydroxybenzaldehyde, dimethyl sulfoxide, cuprous iodide, potassium phosphate, 2-pyridinecarboxylic acid, acetonitrile, N,N-dimethylformamide, chloromethyl methyl ether, sodium dihydrogen phosphate, sodium chlorite, sulfonyl chloride, benzyl bromide, palladium on carbon, palladium acetate, hydrogen, tetrabutylammonium fluoride, potassium tert-butoxide, 2,4-dimethoxybenzaldehyde, triphenylphosphine, bromoethane, boron tribromide, m-chloroperoxybenzoic acid, iodomethane, TBSCl, THF, silica gel, potassium carbonate, methanol, petroleum ether, ethyl acetate, dichloromethane, etc.

[0105] Instruments: ABI Maldi-TOF and Qstar Elite high-resolution mass spectrometry systems; Bruker Avance 600MHz and 400MHz nuclear magnetic resonance spectrometers (Bruker GmbH, Switzerland); Agilent GC-MS; EYLA (SB-1200) rotary evaporator (Shanghai Ailang Instrument Co., Ltd.); HS 7 magnetic stirrer (Shanghai Ailang Instrument Co., Ltd.); YUHUA (ZF-20DAN) dark box ultraviolet analyzer (Shanghai Guanghao Analytical Instrument Co., Ltd.); KQ5200E ultrasonic cleaner (Kunshan Ultrasonic Instrument Co., Ltd.); SB-1200 water bath (Shanghai Ailang Instrument Co., Ltd.); A-1000S water flow vacuum pump (Shanghai Ailang Instrument Co., Ltd.).

[0106] Example 1

[0107] 1. Synthesis of target compound 1

[0108]

[0109] In a 100 mL single-necked flask, 2,6-difluoro-4-hydroxybenzaldehyde (2.0 g, 12.6 mmol), potassium carbonate (1.77 g, 13.0 mmol), N,N-dimethylformamide (5.0 mL), and benzyl bromide (2.2 g, 12.6 mmol) were weighed out. A stir bar was added, and the mixture was stirred at 0°C for 3 hours. 100 mL of ice water was added to quench the reaction. Then, 100.0 mL of ethyl acetate was added for extraction. The organic layer was concentrated and purified by silica gel column chromatography to obtain target compound 1 (2.6 g, 82% yield). The eluent was petroleum ether / ethyl acetate = 19:1. The physicochemical data of the compound are as follows:

[0110] 4-(Benzyloxy)-2,6-difluorobenzaldehyde(1):White solid,mp 147-149℃. 1 H-NMR (600MHz, CDCl3) δ10.20 (s, 1H), 7.47-7.36 (m, 5H), 6.59 (d, J = 10.6Hz, 2H), 5.13 (s, 2H). 13 C-NMR(150MHz, CDCl3)δ183.4,165.5(CF),164.9,163.8(CF),134.8,128.9(2C),128.8,127.6(2C),108.3,99.6,99.5,71.1.HRMS(ESI)calcd.for[C 14 H 10 F2O2+Na] + 271.0547, found 271.0548.

[0111] 2. Synthesis of target compound 2

[0112] First, compound 2a is prepared, and its preparation method is the same as that of compound 1.

[0113] Weigh 2a (1.0 g, 5.8 mmol), pyridinecarboxylic acid (2.2 g, 17.4 mmol), potassium phosphate (3.7 g, 17.4 mmol), and cuprous iodide (3.3 g, 17.4 mmol) into a 100 mL single-necked flask, add a stir bar, evacuate, and add argon gas. Slowly inject benzyl alcohol (1.9 g, 17.4 mmol) and dimethyl sulfoxide (10.0 mL) into the reaction flask, heat at 110 °C, and stir for 10 hours. Cool, add 150 mL of ice water to quench the reaction. Then extract with 150.0 mL of ethyl acetate, concentrate the organic layer, and purify by silica gel column chromatography to obtain the target compound 2b (0.78 g, 52% yield), with petroleum ether / ethyl acetate = 19:1 as the eluent.

[0114] Weigh 2b (0.5 g, 1.9 mmol) and palladium on carbon (10%, 50 mg), place them in a 100 mL single-necked flask, add a stir bar, evacuate, inject methanol, add a hydrogen balloon, and stir at room temperature for 12 hours. Filter the palladium on carbon and concentrate the methanol to obtain compound 2 (0.31 g, 1.8 mmol). The physicochemical data of the compounds are as follows:

[0115]

[0116] 2,6-Difluoro-4-methoxybenzaldehyde(2a):White solid,mp 74-76℃. 1 H-NMR(600MHz, CDCl3)δ10.14(dd,J=19.2,13.8Hz,1H),6.52-6.35(m,2H),3.93-3.77(m,3H).HRMS(ESI)calcd.for[C8H6F2O2+Na] + 195.0234, found 195.0236.

[0117] 2-(Benzyloxy)-6-fluoro-4-methoxybenzaldehyde(2b):Light yellowviscosity. 1 H NMR (600MHz, CDCl3) δ10.37(s,1H),7.46(d,J=7.2Hz,2H),7.42(dd,J=7.2,7.8Hz,1H),7. 38(d,J=7.8Hz,2H),6.34(s,1H),6.28(dd,J=12.6,1.8Hz,1H),5.17(s,2H),3.84(s,3H). 13C NMR(150MHz, CDCl3)δ186.0,166.0(CF),164.2,162.5,135.6,128.8(2C),128.4,127.5,127.2(2C),95.8,94.4,70.9,55.9.HRMS(ESI)calcd.for[C 15 H 13 FO3+Na] + 283.0746, found 283.0749.

[0118] 2-Fluoro-6-hydroxy-4-methoxybenzaldehyde(2):White solid,mp 64-66℃. 1 H-NMR(600MHz, CDCl3)δ11.90(s,1H),10.04(s,1H),6.25-6.15(m,2H),3.90(s,3H).HRMS(ESI)calcd.for[C8H7FO3+Na] + 193.0277, found 193.0278.

[0119] 3. Synthesis of target compound 3

[0120]

[0121] Weigh compound 2 (0.34 g, 2.0 mmol) into a 100 mL single-necked flask, place a magnetic stir bar inside, evacuate the flask, add an argon balloon, and inject 6.0 mL of dry dichloromethane. Add sulfonyl chloride (1.35 g, 10.0 mmol) dropwise at 0°C. After the addition is complete, continue stirring at room temperature for 12 hours. Then add 50 mL of ice water and extract with 50.0 mL of EtOAc. Concentrate the organic solvent layer, eluent by silica gel column chromatography (petroleum ether / ethyl acetate = 17:1), and purify to obtain compound 3 (0.33 g, 70.0%). The physicochemical data of the compounds are as follows:

[0122] 3,5-Dichloro-2-fluoro-6-hydroxy-4-methoxybenzaldehyde(3):Light yellow solid,mp 105-107℃. 1 H-NMR(400MHz, CDCl3)δ12.14(s,1H),10.19(s,1H),4.06(s,3H).HRMS(ESI)calcd.for[C8H5Cl2FO3+Na] + 260.9497, found 260.9499.

[0123] 4. Synthesis of target compound 4

[0124]

[0125] First, compound 4a was prepared using the same method as compound 1.

[0126] Weigh compound 4a (2.0 g, 10.0 mmol) and cesium carbonate (3.26 g, 10.0 mmol) separately into a 100 mL single-necked flask. Add a stir bar, evacuate the flask, and add an argon balloon. Slowly inject benzyl alcohol (1.1 g, 10.0 mmol) and N,N-dimethylformamide (10.0 mL). Stir at 60°C for 12 hours. Cool, then add 100 mL of water, and extract with 100.0 mL of dichloromethane. Concentrate the organic solvent layer, eluent by silica gel column chromatography (petroleum ether / ethyl acetate = 18:1), and purify to obtain compound 4b (2.0 g, 70.0%).

[0127] Take a 100 mL single-necked flask and weigh out compound 4b (1.45 g, 5.0 mmol) and sodium dihydrogen phosphate monohydrate (0.28 g, 2.0 mmol). Measure out acetonitrile (15.0 mL), water (2.5 mL), and hydrogen peroxide (30%, 0.68 g, 6.0 mmol). Stir at 0°C. Slowly add sodium chlorite solution (0.54 g, 6.0 mmol, dissolved in 5 mL water). After addition, stir at room temperature for 12 hours. Then add 50 mL of water and extract with ethyl acetate (2 × 50.0 mL). Concentrate the organic solvent layer and pass it through a silica gel column with petroleum ether / ethyl acetate as the eluent (4:1) to obtain compound 4 (1.1 g, 72.0%). The physicochemical data of the compounds are as follows:

[0128] 2,6-Difluoro-4-(methoxymethoxy)benzaldehyde(4a): White solid, mp 63-65℃. 1 H-NMR (600MHz, CDCl3) δ10.12 (s, 1H), 6.60 (dd, J = 21.0, 10.8Hz, 2H), 5.18 (s, 2H), 3.49 (s, 3H). 13 C-NMR(150MHz, CDCl3)δ183.4,165.2,163.5,163.4,108.68,100.6,100.4,94.52,56.56.HRMS(ESI)calcd.for[C9H8F2O3+Na] + 225.0339, found 225.0337.

[0129] 2-(Benzyloxy)-6-fluoro-4-(methoxymethoxy)benzaldehyde(4b):Lightyellow viscosity. 1 H-NMR (400MHz, CDCl3) δ10.39(s,1H),7.41-7.36(m,5H),6.51(s,1H),6.45(dd,J =12.4,2.0Hz,1H),5.20(s,2H),5.18(s,2H),3.50(s,3H).HRMS(ESI)calcd.for[C 16 H 15 FO4+Na] + 313.0852, found 313.0850.

[0130] 2-(Benzyloxy)-6-fluoro-4-(methoxymethoxy)benzoic acid(4):White solid,mp 101-103℃. 1 H-NMR(400MHz,CD3OD)δ7.46-7.34(m,5H),6.67(s,1H),6.55(dd,J=11.2,2.0Hz,1H),5.25(s,2H),5.21(s,2H),3.51(s,3H).HRMS(ESI)calcd.for[C 16 H 15 FO5+Na] + 329.0801, found 329.0800.

[0131] 5. Synthesis of target compound 5

[0132]

[0133] First, compound 5a was prepared (yield: 90%), using the same method as compound 1.

[0134] Then compound 5 was prepared (yield: 98%), using the same method as compound 2. The physicochemical data of the compounds are as follows:

[0135] Methyl 2-(benzyloxy)-6-fluoro-4-(methoxymethoxy)benzoate(5a):Lightyellow viscosity. 1HNMR(400MHz, CDCl3)δ7.48-7.30(m,5H),6.49-6.43(m,2H),5.15(s,2H),5.13(s,2H),3.90(s,3H),3.47(s,3H).HRMS(ESI)calcd.for[C 17 H 17 FO5+Na] + 343.0958, found 343.0957.

[0136] Methyl 2-fluoro-6-hydroxy-4-(methoxymethoxy)benzoate(5):White solid,mp:70-72℃. 1 HNMR (600MHz, CDCl3) δ11.52(s,1H),6.45(s,1H),6.32(dd,J=12.9,2.4Hz,1H),5.19(s,2H),3.97(s,3H),3.49(s,3H). 13 C NMR(150MHz, CDCl3)δ169.8,164.4,162.9,162.7,99.7,96.9,96.6,94.1,56.44,52.45.HRMS(ESI)calcd.for[C 10 H 11 FO5+Na] + 253.0488, found 253.0486.

[0137] 6. Synthesis scheme of target compound 6

[0138]

[0139] Compound 6a was prepared using the same method as compound 1.

[0140] Compound 6a (2.1 g, 10.0 mmol) was placed in a 100 mL single-necked flask, a stir bar was added, and the flask was evacuated. Then, 20.0 mL of dichloromethane was injected, followed by argon gas. Boron tribromide (1 mol / L dichloromethane solution, 80.0 mL) was added dropwise at 0°C, and the mixture was allowed to warm naturally to room temperature. The mixture was stirred for 3 hours, and the reaction was monitored by TLC until complete. The reaction was quenched with 100.0 mL of ice water, and the mixture was extracted with 100 mL of dichloromethane. The organic solvent layer was separated, concentrated, and the extract was purified by silica gel column chromatography to obtain 6b (1.3 g, 71.0%), using petroleum ether / ethyl acetate (v / v = 10:1) as the eluent.

[0141] Compound 6 was prepared (yield: 78%) using the same method as compound 3. The physicochemical data of the compounds are as follows:

[0142] 2,4-Dihydroxy-6-propylbenzaldehyde(6b):White solid,mp:64-66℃. 1 H NMR (600MHz, CDCl3) δ12.44(s,1H),10.02(s,1H),6.29(s,1H),6.26(s,1H),2.81-2.77(m,2H),1.69-1.61(m,2H),0.98(t,J=7.2Hz,3H). 13 C NMR(150MHz, CDCl3)δ192.9,166.4,164.5,150.3,112.5,110.4,101.3,33.8,25.7,13.9.HRMS(ESI)calcd.for[C 10 H 12 O3+Na] + 203.0684, found 203.0680.

[0143] 3,5-Dichloro-2,4-dihydroxy-6-propylbenzaldehyde(6):White solid,mp:84-86℃. 1 H NMR (600MHz, CDCl3) δ13.03(s,1H),10.12(s,1H),6.67(brs,1H),3.05(t,J=9.0Hz,2H),1.67(dq,J=9.0,7.8Hz,2H),1.07(t,J=7.8Hz,3H). 13 C NMR(150MHz, CDCl3)δ193.3,159.7,154.8,143.7,112.9,112.9,106.6,29.9,24.5,13.9.HRMS(ESI)calcd.for[C 10 H 10 Cl2O3+Na] + 270.9905, found 270.9902.

[0144] 7. Synthesis scheme of target compound 7

[0145]

[0146] Compound 7a was prepared using the same method as compound 1.

[0147] Compound 7 (yield: 77%) was prepared in the same manner as compound 3. The physicochemical data of the compounds are as follows:

[0148] 1,3,5-Trichloro-2,4-dimethoxy-6-propylbenzene(7):Yellow solid,mp:80-82℃. 1 H NMR (600MHz, CDCl3) δ3.90 (s, 6H), 2.94-2.88 (m, 2H), 1.64-1.57 (m, 2H), 1.04 (t, J = 7.2Hz, 3H). 13 C NMR(150MHz, CDCl3)δ151.8(2C),138.8,125.5(2C),122.1,60.6(2C),33.8,21.5,14.1.HRMS(ESI)calcd.for[C 11 H 13 Cl3O2+Na] + 304.9879, found 304.9878.

[0149] 8. Synthesis scheme of target compound 8

[0150]

[0151] Compound 8 (yield: 88%) was prepared using the same method as compound 1. The physicochemical data of compound 8 are as follows:

[0152] 2,4-Bis(benzyloxy)-3,5-dichloro-6-propylbenzaldehyde(8):White solid,mp:110-112℃. 1 HNMR (600MHz, CDCl3) δ10.29 (s, 1H), 7.60 (d, J = 7.2Hz, 2H), 7.47-7.39 (m, 8H), 5.16 (s, 2 H),5.11(s,2H),3.11-3.07(m,2H),1.54(dq,J=15.0,7.2Hz,2H),1.04(t,J=7.2Hz,3H). 13 C NMR (150MHz, CDCl3) δ190.3,158.1,155.9,143.1,135.8,135.1,129.0,128.8(2C),128.7(2C) ,128.6,128.5(5C),127.5,126.6,122.2,77.6,75.1,31.6,23.1,14.3.HRMS(ESI)calcd.for[C 24 H22 Cl2O3+Na] + 451.0844, found 451.0845.

[0153] 9. Synthesis scheme of target compound 9

[0154]

[0155] First, compound 9a was prepared (yield: 80%), using the same method as compound 6b (boron tribromide as twice the substrate equivalent). Then, compound 9b was prepared (yield: 98%), using the same method as compound 3.

[0156] Compound 9b (1.3 g, 5.0 mmol), imidazole (0.34 g, 5.0 mmol), and DMAP (122.0 mg, 1.0 mmol) were placed in a 100 mL single-necked flask, a stir bar was added, and the mixture was evacuated. Dichloromethane (10.0 mL) was added, and an argon balloon was inserted. TBSCl (0.9 g, 6.0 mmol, dissolved in 10 mL of dichloromethane) solution was slowly added dropwise to the reaction mixture. The mixture was stirred at room temperature for 12 hours. Extraction was performed with 50.0 mL of water and 30.0 mL of dichloromethane. The organic solvent layer was separated, concentrated, and the extract was purified by silica gel column chromatography to obtain 9c (1.34 g, 71.0%). The eluent was petroleum ether / ethyl acetate (v / v = 19:1).

[0157] Compound 9c (1.3 g, 3.5 mmol) was placed in a 100 mL single-necked flask, a stir bar was added, and dichloromethane (20.0 mL) was added. m-chloroperoxybenzoic acid (1.2 g, 7.0 mmol) was added in three portions to the reaction mixture. The mixture was stirred at room temperature for 12 hours. Then, 50.0 mL of saturated sodium thiosulfate aqueous solution and 30.0 mL of dichloromethane were added for extraction. The organic solvent layer was separated, concentrated, and the extract was purified by silica gel column chromatography to obtain 9d (1.11 g, 81.0%). The eluent was petroleum ether / ethyl acetate (v / v = 18:1).

[0158] Compound 9d (1.0 g, 2.6 mmol) was placed in a 100 mL single-necked flask, stirred, and mixed with methanol (6.0 mL) and tetrahydrofuran (6.0 mL). The mixture was stirred in an ice-water bath, and lithium hydroxide solution (62.0 mg, 2.6 mmol, in 6.0 mL of water) was added dropwise. The mixture was then heated naturally and stirred for 8 hours. The organic solvent was evaporated to dryness, and the mixture was extracted with 50.0 mL of water and 50.0 mL of dichloromethane. The organic solvent layer was separated, concentrated, and the extract was purified by silica gel column chromatography to obtain compounds 9 and 9e (2:1, total: 0.85 g, 90.0%), using petroleum ether / ethyl acetate (v / v = 17:1). The physicochemical data of the compounds are as follows:

[0159] 2-Hydroxy-4-methoxy-6-propylbenzaldehyde(9a):White solid,mp:50-52℃. 1 H NMR(600MHz,CDCl3)δ12.54(s,1H),10.10(s,1H),6.31(d,J=2.4Hz,1H),6.30(d,J=2.4Hz,1H),3.86(s,3H),2.85-2.80(m,2H),1.68(dt,J=15.0,7.2Hz,2H),1.01(t,J=7.2Hz,3H). 13 C NMR(150MHz,CDCl3)δ192.8,166.7,166.7,148.8,112.5,109.8,98.6,55.6,33.9,25.7,13.9.HRMS(ESI)calcd.for[C 11 H 14 O3+Na] + 217.0841,found 217.0840.

[0160] 3,5-Dichloro-2-hydroxy-4-methoxy-6-propylbenzaldehyde(9b):Lightyellow solid,mp:61-63℃. 1 H NMR(600MHz,CDCl3)δ12.70(s,1H),10.13(s,1H),3.92(s,3H),3.01-2.97(m,2H),1.59(dq,J=15.0,7.2Hz,2H),1.00(t,J=7.2Hz,3H). 13 C NMR(150MHz,CDCl3)δ193.9,159.2,159.1,143.5,120.4,115.2,115.1,60.7,29.8,24.4,13.8.HRMS(ESI)calcd.for[C 11 H 12 Cl2O3+Na] + 285.0061,found 285.0060.

[0161] 2-((Tert-butyldimethylsilyl)oxy)-3,5-dichloro-4-methoxy-6-propylphenyl formate(9d):Light yellow viscosity. 1H NMR(600MHz, CDCl3)δ8.22(s,1H),3.90(s,3H),2.67-2.63(m,2H),1.58-1.52( m,2H),1.03(s,9H),0.98(t,J=7.2Hz,3H),0.24(s,6H).HRMS(ESI)calcd.for[C 17 H 26 Cl2O4Si+Na] + 415.0875, found 415.0873.

[0162] 2-((Tert-butyldimethylsilyl)oxy)-3,5-dichloro-4-methoxy-6-propylphenol(9):Light yellow viscosity. 1 H NMR (400MHz, CDCl3) δ5.39 (s, 1H), 3.85 (s, 3H), 2.76 (t, J = 7.2Hz, 2H), 1.62-1.51 (m,2H),1.06(s,9H),0.99(t,J=7.2Hz,3H),0.28(s,6H).HRMS(ESI)calcd.for[C 16 H 26 Cl2O3Si+Na] + 387.0926, found 387.0924.

[0163] 10. Synthesis scheme of target compound 10

[0164]

[0165] First, compound 10a was prepared (yield: 72%), using the same method as compound 1.

[0166] Then compound 10b was prepared (yield: 78%), using the same method as compound 9d.

[0167] Finally, compound 10 was prepared (yield: 75%), using the same method as compound 9. The physicochemical data of the compounds are as follows:

[0168] 3,5-Dichloro-4-methoxy-2-(methoxymethoxy)-6-propylbenzaldehyde(10a):Light yellow solid,mp:70-72℃. 1H NMR (400MHz, CDCl3) δ10.42(s,1H),5.18(s,2H),3.97(s,3H),3.62(s,3H),3.11-3.04(m,2H),1.57(dq,J=15.0,7.6Hz,2H),1.05(t,J=7.6Hz,3H). 13 C NMR(100MHz, CDCl3)δ190.9,157.0,156.9,142.8,127.3,126.8,121.5,101.0,60.8,58.4,31.6,23.1,14.3.HRMS(ESI)calcd.for[C 13 H 16 Cl2O4+Na] + 329.0323, found 329.0320.

[0169] 3,5-Dichloro-4-methoxy-2-(methoxymethoxy)-6-propylphenol(10):Lightyellow viscosity. 1 HNMR (400MHz, CDCl3) δ7.07(brs,1H),5.11(s,2H),3.84(s,3H),3.63(s,3H),2.80-2.75(m,2H),1.64-1.54(m,2H),0.99(t,J=7.2Hz,3H). 13 C NMR(100MHz, CDCl3)δ145.6,145.1,140.7,127.8,125.6,119.7,100.2,60.6,57.8,29.6,21.8,14.1.HRMS(ESI)calcd.for[C 12 H 16 Cl2O4+Na] + 317.0323, found 317.0321.

[0170] 11. Synthetic schemes for target compounds 11 and 12

[0171]

[0172] First, compound 11 was prepared (yield: 77%), using the same method as compound 1.

[0173] Then compound 12a was prepared (yield: 73%), using the same method as compound 9d.

[0174] Finally, compound 12 was prepared (yield: 74%), using the same method as compound 9. The physicochemical data of the compounds are as follows:

[0175] 2-(Benzyloxy)-3,5-dichloro-4-methoxy-6-propylbenzaldehyde(11):Lightyellow solid,mp:75-77℃. 1 H NMR(600MHz, CDCl3)δ10.27(s,1H),7.46-7.36(m,5H),5.10(s,2H),4.00(s,3 H), 3.08 (t, J = 7.2Hz, 2H), 1.53 (dq, J = 15.0, 7.2Hz, 2H), 1.04 (t, J = 7.2Hz, 3H). 13 C NMR (150MHz, CDCl3) δ190.3,158.2,157.3,143.1,135.2,128.9,128.8(2C),128. 7(2C),127.2,126.4,121.8,77.6,60.9,31.6,23.0,14.3.HRMS(ESI)calcd.for[C 18 H 18 Cl2O3+Na] + 375.0531, found 375.0530.

[0176] 2-(Benzyloxy)-3,5-dichloro-4-methoxy-6-propylphenyl formate(12a):Light yellow viscosity. 1 H NMR(600MHz, CDCl3)δ8.20(s,1H),7.51-7.35(m,5H),5.01(s,2H),3.93(s,3H),2.70-2 .65(m,2H),1.55(dq,J=15.0,7.2Hz,2H),0.98(t,J=7.2Hz,3H).HRMS(ESI)calcd.for[C 18 H 18 Cl2O4+Na] + 391.0480, found 391.0484.

[0177] 2-(Benzyloxy)-3,5-dichloro-4-methoxy-6-propylphenol(12):Light yellowviscosity. 1H NMR (600MHz, CDCl3) δ7.48-7.40(m,5H),5.50(s,1H),5.09(s,2H),3.89(s,3H ), 2.73(t,J=7.2Hz,2H), 1.55(dq,J=15.0,7.2Hz,2H), 0.95(t,J=7.2Hz,3H). 13 C NMR(150MHz, CDCl3)δ145.8,145.0,140.6,136.1,129.1,128.9(2C),128.7(2C),126.8,125.2,119.6,76.0,60.8,29.3,21.7,13.9.HRMS(ESI)calcd.for[C 17 H 18 Cl2O3+Na] + 363.0531, found 363.0531.

[0178] 12. Synthesis scheme of target compound 13

[0179]

[0180] First, compound 13a was prepared (yield: 76%), using the same method as compound 4.

[0181] Compound 13a (1.1 g, 3.0 mmol), 2,2'-bipyridine (0.47 g, 3.0 mmol), and cuprous oxide (0.43 g, 3.0 mmol) were placed in a 100 mL single-necked flask, a stir bar was added, vacuum was applied, and diethylene glycol dimethyl ether (10.0 mL) was injected. An argon balloon was added. The mixture was stirred at 165°C for 12 hours. The organic solvent was evaporated to dryness, and 100.0 mL of dichloromethane was added. The mixture was filtered through diatomaceous earth, and the organic solvent was concentrated. The extract was purified by silica gel column chromatography to obtain 13b (0.6 g, 62.0%), with petroleum ether / ethyl acetate (v / v = 19:1) as the eluent. Finally, compound 13 (yield: 98%) was prepared using the same method as compound 2. The physicochemical data of the compounds are as follows:

[0182] 2-(Benzyloxy)-3,5-dichloro-4-methoxy-6-propylbenzoic acid(13a):Whitesolid,mp:125-127℃. 1H NMR(600MHz,CD3OD)δ7.51(d,J=7.2Hz,2H),7.40(dd,J=7.2,7.2Hz,2H),7.36(t,J=7.2Hz,1H),5.08(s,2H),3.92(s,3H),2.78-2.73(m,2H),1.67(dq,J=15.0,7.5Hz,2H),1.02(t,J=7.5Hz,3H). 13 C NMR(150MHz,CD3OD)δ168.2,153.8,150.6,137.2,136.5,128.7,128.0(4C),127.9,125.1,121.4,76.0,59.8,33.3,22.6,13.1.HRMS(ESI)calcd.for[C 18 H 18 Cl2O4+Na] + 391.0480,found 391.0482.

[0183] 1-(Benzyloxy)-2,4-dichloro-3-methoxy-5-propylbenzene(13b):Colorlessviscosity. 1 H NMR(600MHz,CDCl3)δ7.48(d,J=7.2Hz,2H),7.42(dd,J=7.8,7.2Hz,2H),7.35(t,J=7.2Hz,1H),6.66(s,1H),5.15(s,2H),3.92(s,3H),2.69-2.65(m,2H),1.67-1.59(m,2H),0.96(t,J=7.2Hz,3H). 13 C NMR(150MHz,CDCl3)δ153.3,153.2,139.9,136.3,128.6(2C),128.1,127.2(2C),121.1,116.2,110.9,71.2,60.5,36.0,22.8,13.8.HRMS(ESI)calcd.for[C 17 H 18 Cl2O2+Na] + 347.0582,found 347.0582.

[0184] Methyl 2,4-Dichloro-3-methoxy-5-propylphenol(13):Colorlessviscosity. 1H NMR (600MHz, CDCl3) δ6.73 (s, 1H), 5.73 (brs, 1H), 3.90 (s, 3H), 2.68-2.63 (m, 2H), 1.67-1.59 (m, 2H), 0.98 (t, J = 7.2Hz, 3H). 13 C NMR(150MHz, CDCl3)δ152.3,150.5,140.8,120.2,112.9,112.7,60.6,35.6,22.7,13.8.HRMS(ESI)calcd.for[C 10 H 12 Cl2O2+Na] + 257.0112, found 257.0113.

[0185] 13. Synthesis scheme of target compound 14

[0186]

[0187] Compound 14 (yield: 88%) was prepared using the same method as compound 1. The physicochemical data of compound 14 are as follows:

[0188] Benzyl 2-(benzyloxy)-3,5-dichloro-4-methoxy-6-propylbenzoate(14):Colorless viscosity. 1 HNMR(600MHz, CDCl3)δ7.44-7.31(m,10H),5.28(s,2H),5.05(s,2H),3.93(s,3H),2 .62-2.57(m,2H),1.57-1.51(m,2H),0.87(t,J=7.2Hz,3H).HRMS(ESI)calcd.for[C 25 H 24 Cl2O4+Na] + 481.0949, found 481.0947.

[0189] 14. Synthesis scheme of target compound 15

[0190]

[0191] First, compound 15a was prepared using the same method as compound 1.

[0192] Compound 15a (0.72 g, 2.0 mmol), elemental iodine (0.76 g, 3.0 mmol), palladium acetate (45.0 mg, 0.2 mmol), and iodobenzene diacetate (0.97 g, 3.0 mmol) were placed in a 100.0 mL single-necked flask, a stir bar was added, and anhydrous DMF (5.0 mL) was added. The mixture was stirred at 110 °C for 12 hours. The reaction was quenched by adding 50 mL of saturated sodium carbonate solution, followed by extraction with 50.0 mL of ethyl acetate. The organic solvent layer was separated, concentrated, and the extract was purified by silica gel column chromatography to obtain 15a (0.44 g, 45.0%). The eluent was petroleum ether / ethyl acetate (v / v = 16:1). The physicochemical data of the compound are as follows:

[0193] Benzyl 4-(benzyloxy)-2-propylbenzoate(15a):White solid,mp:79-81℃. 1 HNMR (600MHz, CDCl3) δ8.00(d,J=8.7Hz,1H),7.47(t,J=7.8Hz,4H),7.45-7.40(m,4H),7.37(t,J=7.2Hz,2H),6.88(d,J=2.4 Hz,1H),6.85(dd,J=8.7,2.4Hz,1H),5.35(s,2H),5.13(s,2H),3.01-2.95(m,2H),1.68-1.60(m,2H),0.96(t,J=7.3Hz,3H). 13 C NMR (150MHz, CDCl3) δ166.8,161.5,147.7,136.4,136.3,133.3,128.7(2C),128.6(2C),128.3(2C), 128.2,128.1,127.5(2C),121.7,117.3,111.7,69.9,66.3,36.9,24.8,14.2.HRMS(ESI)calcd.for[C 24 H 24 O3+Na] + 383.1623, found 383.1620.

[0194] Benzyl 4-(benzyloxy)-2-iodo-6-propylbenzoate(15):White solid,mp:80-82℃. 1H NMR (600MHz, CDCl3) δ8.42(s,1H),7.52(d,J=7.5Hz,2H),7.47(d,J=7.2Hz,2H),7.45-7.41(m,4H),7.40-7.35( m,2H),6.71(s,1H),5.34(s,2H),5.22(s,2H),2.93(t,J=7.8Hz,2H),1.62-1.56(m,2H),0.91(t,J=7.2Hz,3H). 13 C NMR (150MHz, CDCl3) δ165.6,159.7,147.9,142.3,136.0,135.9,128.7(4C),128.4(2C),128.3 ,128.1,127.0(2C),123.5,114.4,82.6,70.8,66.7,36.9,24.7,14.0.HRMS(ESI)calcd.for[C 24 H 23 IO3+Na] + 509.0590, found 509.0591.

[0195] 15. Synthesis scheme of target compound 16

[0196]

[0197] First, compound 16a was prepared (yield: 70%), using the same method as compound 10;

[0198] Compound 16b was prepared (yield: 68%) by the same method as 2b.

[0199] Compound 16c was prepared (yield: 65%, heating temperature: 110 degrees Celsius) by the same method as compound 4b.

[0200] Compound 16d was prepared (yield: 85%), using the same method as compound 4;

[0201] Compound 16 was prepared (yield: 87%) by the same method as compound 5a.

[0202] The physicochemical data of the compound are as follows:

[0203] 4-Methoxy-2-(methoxymethoxy)-6-propylphenol(16a):Colorless oil. 1H NMR(600MHz,CDCl3)δ6.62(d,J=3.0Hz,1H),6.41(d,J=3.0Hz,1H),5.62(brs,1H),5.19(s,2H),3.76(s,3H),3.52(s,3H),2.65-2.59(m,2H),1.66(dt,J=15.0,7.5Hz,2H),1.00(t,J=7.5Hz,3H). 13 C NMR(150MHz,CDCl3)δ152.6,144.5,138.3,129.4,108.4,100.1,96.0,56.4,55.7,32.2,22.9,14.1.HRMS(ESI)calcd.for[C 12 H 18 O4+Na] + 249.1103,found249.1102.

[0204] 2-Fluoro-4-methoxy-6-(4-methoxy-2-(methoxymethoxy)-6-propylphenoxy)benzaldehyde(16b):Colorless viscosity. 1 H NMR(600MHz,CDCl3)δ10.53(s,1H),6.66(d,J=3.0Hz,1H),6.48(d,J=3.0Hz,1H),6.29(dd,J=12.6,1.5Hz,1H),5.88(d,J=1.5Hz,1H),5.08(s,2H),3.82(s,3H),3.71(s,3H),3.34(s,3H),2.48(t,J=7.2Hz,2H),1.58(dt,J=15.0,7.5Hz,2H),0.91(t,J=7.5Hz,3H). 13 C NMR(150MHz,CDCl3)δ185.9,165.7,164.0,163.3,157.6,149.9,137.2,134.8,108.3,107.3,101.0,96.2,95.3,94.9,56.2,55.8,55.6,32.4,23.3,14.0.HRMS(ESI)calcd.for[C 20 H 23 FO6+Na] + 401.1376,found 401.1374.

[0205] 2-(Benzyloxy)-4-methoxy-6-(4-methoxy-2-(methoxymethoxy)-6-propylphenoxy)benzaldehyd e(16c):Colorless viscosity. 1 H NMR(600MHz,CDCl3)δ10.67(s,1H),7.54(d,J=7.8Hz,2H),7.43(dd,J=7.8,7.2Hz,2H),7.35(t,J=7.2Hz,1H),6.66(d,J=3.0Hz,1H),6.48(d,J=3.0Hz,1H),6.17(d,J=2.1Hz,1H),5.70(d,J=2.1Hz,1H),5.21(s,2H),5.11(brs,2H),3.82(s,3H),3.66(s,3H),3.36(s,3H),2.48-2.49(m,2H),1.58-1.61(m,2H),0.91(t,J=7.5Hz,3H). 13 C NMR(150MHz,CDCl3)δ187.3,165.6,163.9,162.4,157.3,150.1,137.4,136.3,135.3,128.7(2C),127.9,126.9(2C),109.1,107.9,101.2,95.1,92.8,92.2,70.6,56.2,55.6,55.4,32.4,23.2,14.0.HRMS(ESI)calcd.for[C 27 H 30 O7+Na] + 489.1889,found 489.1887.

[0206] Methyl 2-(benzyloxy)-4-methoxy-6-(4-methoxy-2-(methoxymethoxy)-6-propylphenoxy)benzoate(16):White solid,mp:90-92℃. 1H NMR (600MHz, CDCl3) δ7.45(d,J=7.5Hz,2H),7.40(dd,J=7.5,7.2Hz,2H),7.33(t,J =7.2Hz,1H),6.65(d,J=3.0Hz,1H),6.47(d,J=3.0Hz,1H),6.17(d,J=2.1Hz,1H),5 .71(d,J=2.1Hz,1H),5.13(s,2H),5.09(s,2H),3.91(s,3H),3.82(s,3H),3.63(s, 3H), 3.39 (s, 3H), 2.49 (t, J = 7.2Hz, 2H), 1.62-1.53 ​​(m, 2H), 0.92 (t, J = 7.2Hz, 3H). 13 CNMR (150MHz, CDCl3) δ166.6,162.1,157.9,157.8,157.2,150.4,137.8,136.7,135.6,128.5(2C),127.8,126.9(2 C),108.2,106.3,101.6,95.3,92.8,92.3,70.5,56.2,55.5,55.3,52.2,32.4,23.3,13.9.HRMS(ESI)calcd.for[C 28 H 32 O8+Na] + 519.1995, found 519.1993.

[0207] 16. Synthesis scheme of target compound 17

[0208]

[0209] Compound 17 (yield: 97%) was prepared by the same method as in compound 2; the physicochemical data of compound 17 are as follows:

[0210] Methyl 2-hydroxy-4-methoxy-6-(4-methoxy-2-(methoxymethoxy)-6-propylphenoxy)benzoate(17):White solid,mp:99-101℃. 1H NMR (600MHz, CDCl3) δ12.03(s,1H),6.66(d,J=3.0Hz,1H),6.48(d,J=3.0Hz,1H),6.14(d,J=2.4Hz,1H),5.59(d,J=2.4Hz,1H),5.14(d,J=4.2H z,1H),5.05(d,J=4.2Hz,1H),3.95(s,3H),3.82(s,3H),3.70(s,3H),3. 38(s,3H),2.53-2.35(m,2H),1.60-1.55(m,2H),0.91(t,J=7.5Hz,3H). 13 C NMR (150MHz, CDCl3) δ171.8,165.6,165.1,161.3,157.2,149.9,137.3,135.5,108.2,101. 4,96.5,95.0,94.1,93.4,56.2,55.6,55.4,52.1,32.6,23.3,14.0.HRMS(ESI)calcd.for[C 21 H 26 O8+Na] + 429.1525, found 429.1520.

[0211] 17. Synthesis scheme of target compound 18

[0212]

[0213] First, compound 18a is prepared by following a similar procedure to that of compound 10.

[0214] Next, compound 4 (1.53 g, 5.0 mmol), dicyclohexylcarbodiimide (2.06 g, 10.0 mmol), and DMAP (1.22 g, 10.0 mmol) were placed in a 100.0 mL single-necked flask, a stir bar was added, an anhydrous toluene (15.0 mL) was injected under vacuum, and the mixture was stirred at 40 °C for 2 hours. A solution of 18a (1.48 g, 5.0 mmol, dissolved in 10.0 mL toluene) was slowly added dropwise, and the mixture was stirred at 55 °C for 12 hours after the addition was complete. The mixture was cooled, and the reaction was quenched with 100 mL of ice water. Then, 100.0 mL of ethyl acetate was added to extract the reaction mixture. The organic solvent layer was separated, concentrated, and the extract was purified by silica gel column chromatography to obtain 18 (1.89 g, 65.0%). The eluent was petroleum ether / ethyl acetate (v / v = 15:1). The physicochemical data of the compounds are as follows:

[0215] 2-((Tert-butyldimethylsilyl)oxy)-4-methoxy-6-propylphenol(18a):Colorless oil. 1 H NMR(600MHz,CDCl3)δ6.38(brs,2H),5.24(s,1H),3.77(s,3H),2.68-2.64(m,2H),1.75-1.67(m,2H),1.08(s,9H),1.03(t,J=7.5Hz,3H),0.33(s,6H).HRMS(ESI)calcd.for[C 16 H 28 O3Si+Na] + 319.1705,found 319.1700.

[0216] 2-((Tert-butyldimethylsilyl)oxy)-4-methoxy-6-propylphenyl2-(benzyloxy)-6-fluoro-4-(methoxymethoxy)benzoate(18):Colorless viscosity. 1 HNMR(400MHz,CDCl3)δ7.46(d,J=6.8Hz,2H),7.39-7.30(m,3H),6.62(d,J=2.8Hz,1H),6.54-6.48(m,3H),5.20(s,2H),5.14(s,2H),3.65(s,3H),3.51(s,3H),2.61-2.55(m,2H),1.68-1.59(m,2H),0.98(t,J=7.2Hz,3H),0.93(s,10H),0.06(s,6H). 13 C NMR(100MHz,CDCl3)δ163.5,161.6,161.1,160.9,159.,153.3,141.7,138.9,135.9,128.6(2C),128.0,127.3(2C),113.3,105.5,97.4,96.7,96.4,94.5,70.9,56.4,55.5,32.7,25.9,23.1,18.5,14.0,-4.1.HRMS(ESI)calcd.for[C 32 H 41 FO7Si+Na] + 607.2503,found 607.2504.

[0217] 18. Synthesis scheme of target compound 19

[0218]

[0219] Compound 18 (1.46 g, 2.5 mmol) was placed in a 100.0 mL single-necked flask, a stir bar was added, and tetrahydrofuran (15.0 mL) was added. The mixture was stirred at room temperature. Tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 10.0 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The organic solvent was evaporated at room temperature, 100 mL of ice water was added, and then 100.0 mL of ethyl acetate was added to extract the reaction mixture. The organic solvent layer was separated, concentrated, and the extract was purified by silica gel column chromatography to obtain 19 (0.88 g, 75.0%). The eluent was petroleum ether / ethyl acetate (v / v = 14:1). The physicochemical data of the compounds are as follows:

[0220] 2-Hydroxy-4-methoxy-6-propylphenyl 2-(benzyloxy)-6-fluoro-4-(methoxymethoxy)benzoate(19):Colorless viscosity. 1 H NMR (400MHz, CDCl3) δ7.45-7.35(m,5H),6.58(brs,1H),6.55(dd,J=12.0,2.0Hz,1H),6.42(d,J=2.8Hz,1H),6.38(d,J=2.8Hz,1H),5.97(brs, 1H),5.26(s,2H),5.18(s,2H),3.78(s,3H),3.48(s,3H),2.54-2.48(m,2H),1.65-1.61(m,2H),0.92(t,J=7.2Hz,3H).HRMS(ESI)calcd.for[C 26 H 27 FO7+Na] + 493.1639, found 493.1638.

[0221] 19. Synthesis scheme of target compound 20

[0222]

[0223] Compound 20 can be prepared from compound 19 using the same procedure as compound 2b, with a yield of 64%. Alternatively, copper tetraacetonitrile hexafluorophosphate can be used instead of cuprous iodide as the catalyst, with the same operating conditions, to prepare 20, with a yield of 60%. The physicochemical data of the compounds are as follows: 1-(Benzyloxy)-7-methoxy-3-(methoxymethoxy)-9-propyl-11H-dibenzo[b,e][1,4]dioxepin-11-one(20): Colorless viscosity. 1 H NMR(400MHz, CDCl3) δ7.49(d,J=7.6Hz,2H),7.39(t,J=7.6Hz,2H),7.36-7.30( m,1H),6.65(d,J=2.8Hz,1H),6.59(d,J=2.8Hz,1H),6.55(d,J=2.0Hz,1H),6.51 (d,J=2.0Hz,1H),5.18(s,2H),5.16(s,2H),3.79(s,3H),3.48(s,3H),2.72(t, J=7.6Hz,2H),1.69-1.60(m,2H),0.96(t,J=7.2Hz,3H).HRMS(ESI)calcd.for[C 26 H 26 O7+Na] + 473.1576, found 473.1572.

[0224] 20. Synthesis scheme of target compound 21

[0225]

[0226] Compound 21 can be prepared from compound 20 by the same procedure as compound 2, with a reaction yield of 98%. The physicochemical data of compound 21 are as follows: 1-Hydroxy-7-methoxy-3-(methoxymethoxy)-9-propyl-11H-dibenzo[b,e][1,4]dioxepin-11-one(21): White solid, mp: 69-71℃. 1H NMR (400MHz, CDCl3) δ11.03(s,1H),6.65(d,J=2.8Hz,1H),6.61(d,J=2.8Hz,1H),6.50(d,J=2.0Hz,1H),6.48(d,J =2.0Hz,1H),5.21(s,2H),3.80(s,3H),3.49(s,3H),2.77-2.70(m,2H),1.72-1.61(m,2H),0.98(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ168.0,165.5,164.0,161.5,157.3,150.2,136.4,136.3,112.6, 103.9,100.8,100.7,99.8,94.1,56.5,55.7,32.4,23.5,13.8.HRMS(ESI)calcd.for[C 19 H 20 O7+Na] + 383.1107, found 383.1101.

[0227] 21. Synthesis scheme of target compound 22

[0228]

[0229] Compound 21 (540.0 mg, 1.5 mmol) was placed in a 100.0 mL single-necked flask, stirred, evacuated, and argon balloon was added. Dry dichloromethane (15.0 mL), anhydrous pyridine (240.0 mg, 3.0 mmol), and trifluoromethanesulfonic anhydride (564.0 mg, 2.0 mmol) were added separately, and the mixture was stirred at 50°C for 3 hours. The reaction was quenched with 100 mL of ice water, followed by extraction with 100.0 mL of ethyl acetate. The organic solvent layer was separated, concentrated, and the extract was purified by silica gel column chromatography to obtain 22a (627.0 mg, 85.0%). The eluent was petroleum ether / ethyl acetate (v / v = 15:1).

[0230] Lithium chloride (42.0 mg, 1.0 mmol) was placed in a 100.0 mL single-necked flask, a stir bar was added, and the flask was dried in an oven at 100°C for 30 minutes. It was then removed and cooled. Triphenylphosphine (262.0 mg, 1.0 mmol) and bis(triphenylphosphine) palladium dichloride (140.0 mg, 0.2 mmol) were rapidly added to the reaction flask. The flask was evacuated, and the temperature was maintained above 60°C using a hot air gun (this procedure can also be performed at room temperature in a glove box). 22a (492.0 mg, 1.0 mmol, dissolved in 10 mL anhydrous DMF) was injected, an argon balloon was added, and allyltributyltin (496.0 mg, 1.5 mmol) was added. The mixture was stirred at 100°C for 12 hours. The reaction was cooled, quenched with 100 mL of saturated sodium fluoride aqueous solution, and then extracted with 100.0 mL of ethyl acetate. The organic solvent layer was separated, concentrated, and the extract was purified by silica gel column chromatography to obtain 22 (245.0 mg, 64.0%). The eluent was petroleum ether / ethyl acetate (v / v = 15:1). The physicochemical data of the compound are as follows:

[0231] 7-Methoxy-3-(methoxymethoxy)-11-oxo-9-propyl-11H-dibenzo[b,e][1,4]dioxepin-1-yl trifluoromethanesulfonate(22a):Colorless viscosity. 1 H NMR (400MHz, CDCl3) δ6.99(d,J=2.4Hz,1H),6.86(d,J=2.4Hz,1H),6.67(d,J=3.0Hz,1H),6.63(d,J=3.0Hz ,1H),5.25(s,2H),3.80(s,3H),3.50(s,3H),2.74-2.67(m,2H),1.72-1.61(m,2H),0.98(t,J=7.2Hz,3H). 13 CNMR (100MHz, CDCl3) δ162.9,161.6,159.8,157.0,151.0,150.1,136.7,135.6,120.2(CF),117.0( CF),112.9,110.4,108.8,107.6,104.1,94.8,56.7,55.7,32.3,23.1,13.8.HRMS(ESI)calcd.for[C 20 H 19 F3O9S+Na] + 515.0600, found 515.0604.

[0232] 1-Allyl-7-methoxy-3-(methoxymethoxy)-9-propyl-11H-dibenzo[b,e][1,4]dioxepin-11-one(22):Colorless viscosity. 1 H NMR (400MHz, CDCl3) δ6.81(d,J=2.0Hz,1H),6.79(d,J=2.0Hz,1H),6.67(d,J=2.8Hz,1H),6.57(d,J=2.8Hz,1H),5.95-5.85(m,1H),5.21(s,2H),5.1 0-5.06(m,1H),5.04(s,1H),3.79(s,3H),3.65(d,J=6.6Hz,2H),3.49(s,3 H),2.71-2.64(m,2H),1.62(dt,J=15.0,7.2Hz,2H),0.95(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ163.6,163.1,160.8,156.6,151.7,146.6,136.4,136.3,135.8,116.7,115 .8,114.8,112.4,105.5,104.1,94.2,56.4,55.7,38.0,32.4,23.4,13.8.HRMS(ESI)calcd.for[C 22 H 24 O6+Na] + 407.1471, found 407.1470.

[0233] 22. Synthesis scheme of target compound 23

[0234]

[0235] Compound 23 can be prepared from compound 22 (using ethyl acetate as the reaction solvent) under the same conditions as compound 2, with a yield of 98%. The physicochemical data of compound 23 are as follows:

[0236] 7-Methoxy-3-(methoxymethoxy)-1,9-dipropyl-11H-dibenzo[b,e][1,4]dioxepin-11-one(23):White solid,mp:53-55℃. 1H NMR (400MHz, CDCl3) δ6.77(brs,2H),6.66(d,J=2.8Hz,1H),6.57(d,J=2.8Hz,1H),5.21(s,2H),3.7 9(s,3H),3.49(s,3H),2.87-2.80(m,2H),2.73-2.66(m,2H),1.68-1.56(m,4H),1.00-0.89(m,6H). 13 C NMR (100MHz, CDCl3) δ163.6,163.0,160.6,156.6,151.7,149.4,136.6,135.7,115.5,114.8,11 2.4,105.2,104.1,94.2,56.4,55.7,35.9,32.4,24.7,23.4,14.0,13.7.HRMS(ESI)calcd.for[C 22 H 26 O6+Na] + 409.1627, found 409.1625.

[0237] 23. Synthesis scheme of target compound 24

[0238]

[0239] Compound 23 (386.0 mg, 1.0 mmol) was placed in a 100.0 mL single-necked flask, a stir bar was added, and ethyl acetate (15.0 mL) was added. The mixture was stirred at room temperature. Concentrated hydrochloric acid (1.0 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour after the addition was complete. 100 mL of ice water was added, followed by 100.0 mL of ethyl acetate to extract the reaction mixture. The organic solvent layer was separated, concentrated, and the extract was purified by silica gel column chromatography to obtain 24 (294.0 mg, 86.0%). The eluent was petroleum ether / ethyl acetate (v / v = 8:1). The physicochemical data of the compounds are as follows:

[0240] 3-Hydroxy-7-methoxy-1,9-dipropyl-11H-dibenzo[b,e][1,4]dioxepin-11-one(24):White solid,mp:69-71℃. 1 H NMR (400MHz, CDCl3) δ6.65-6.60 (m, 3H), 6.57 (d, J = 2.8Hz, 1H), 3.78 (s, 3H), 2.8 4-2.78(m,2H),2.67(t,J=7.6Hz,2H),1.66-1.55(m,4H),0.92(t,J=7.2Hz,6H). 13CNMR (100MHz, CDCl3) δ165.2,163.4,160.5,156.8,151.6,150.0,136.5,135.7,115.3,112 .9,112.4,105.2,104.0,55.7,35.9,32.3,24.6,23.4,14.0,13.7.HRMS(ESI)calcd.for[C 20 H 22 O5+Na] + 365.1365, found 365.1361.

[0241] 24. Synthetic schemes for target compounds 25-28

[0242]

[0243] Compounds 25-28 (yield: 20%-40%) were prepared using the same method as compound 3. Using compound 24 as a starting material, the reaction was carried out at room temperature with anhydrous dichloromethane as solvent and sulfonyl chloride as a substrate in 10 equivalents. The reaction was completed in 12 hours at room temperature, and the compounds were purified by silica gel column chromatography to obtain 25-28. The physicochemical data of the compounds are as follows:

[0244] 2,8-Dichloro-3-hydroxy-7-methoxy-1,9-dipropyl-11H-dibenzo[b,e][1,4]dioxepin-11-one(25):Light yellow solid,mp:80-82℃. 1 H NMR (400MHz, CDCl3) δ6.83(s,1H),6.72(s,1H),3.90(s,3H),2.95-2.87(m,4H),1.71-1.57(m,4H),1.04-0.96(m,6H). 13 CNMR (100MHz, CDCl3) δ162.5,161.3,155.3,152.7,149.6,145.8,136.6,134.4,119.8,119 .1,115.1,105.5,102.2,56.6,33.5,29.7,23.0,22.1,14.2,13.9.HRMS(ESI)calcd.for[C 20 H 20 Cl2O5+Na] + 433.0585, found 433.0580.

[0245] 4,8-Dichloro-3-hydroxy-7-methoxy-1,9-dipropyl-11H-dibenzo[b,e][1,4]dioxepin-11-one(26):Light yellow solid,mp:74-76℃. 1 H NMR(400MHz,CDCl3)δ6.88(s,1H),6.82(s,1H),3.90(s,3H),2.93-2.87(m,2H),2.82-2.76(m,2H),1.64-1.56(m,4H),0.99-0.92(m,6H). 13 C NMR(100MHz,CDCl3)δ162.3,157.5,155.2,152.6,149.3,147.2,136.6,134.4,120.1,115.1,114.7,109.4,102.8,56.6,35.5,29.8,24.5,22.1,13.9,13.9.HRMS(ESI)calcd.for[C 20 H 20 Cl2O5+Na] + 433.0585,found 433.0581.

[0246] 2,4,8-Trichloro-3-hydroxy-7-methoxy-1,9-dipropyl-11H-dibenzo[b,e][1,4]dioxepin-11-one(27):Light yellow solid,mp:109-111℃. 1 H NMR(400MHz,CDCl3)δ6.89(s,1H),6.46(brs,1H),3.90(s,3H),2.95-2.85(m,4H),1.69-1.55(m,4H),1.05-0.94(m,6H). 13 C NMR(100MHz,CDCl3)δ161.8,156.2,152.7,151.7,149.2,143.2,136.4,134.3,120.3,119.6,115.8,110.8,102.8,56.6,33.2,29.8,23.0,22.1,14.1,13.9.HRMS(ESI)calcd.for[C 20 H 19 Cl3O5+Na] + 467.0196,found467.0193.

[0247] 2,6,8-Trichloro-3-hydroxy-7-methoxy-1,9-dipropyl-11H-dibenzo[b,e][1,4]dioxepin-11-one(28):Light yellow solid,mp:115-117℃. 1 H NMR (400MHz, CDCl3) δ7.03(s,1H),3.89(s,3H),2.94-2.83(m,4H),1.70-1.55(m,4H),1.02(t,J=5.6Hz,3H),0.99(t,J=5.6Hz,3H). 13 C NMR (100MHz, CDCl3) δ161.4,160.6,155.6,150.2,146.2,145.9,140.3,132.2,126.6,119 .5,119.4,114.6,106.4,60.8,33.5,29.8,23.0,22.1,14.2,13.9.HRMS(ESI)calcd.for[C 20 H 19 Cl3O5+Na] + 467.0196, found 467.0190.

[0248] 25. Synthesis scheme of target compound 29

[0249]

[0250] Compound 27 (45.0 mg, 0.1 mmol) was placed in a 25.0 mL single-necked flask, a stir bar was added, and the flask was evacuated. Sulfonyl chloride (0.3 mL) was added dropwise, and an argon balloon was added. The mixture was stirred at room temperature for 12 hours. 50 mL of ice water was added, followed by 50.0 mL of dichloromethane to extract the reaction mixture. The organic solvent layer was separated, concentrated, and the extract was purified by silica gel column chromatography to obtain 29 (39.0 mg, 81.0%). The eluent was petroleum ether / ethyl acetate (v / v = 10:1). 29 can also be prepared from 28 using the same procedure. The physicochemical data of the compounds are as follows:

[0251] 2,4,6,8-Tetrachloro-3-hydroxy-7-methoxy-1,9-dipropyl-11H-dibenzo[b,e][1,4]dioxepin-11-one(29):Light yellow solid,mp:177-179℃. 1H NMR (400MHz, DMSO-d6) δ5.75(brs,1H),3.81(s,3H),2.85-2.70(m,4H),1.60-1.45(m,4H),0.95-0.85(m,6H). 13 C NMR (100MHz, DMSO-d6) δ160.9,156.1,155.1,150.3,146.7,143.6,140.1,132. 2,126.7,121.7,119.1,113.5,112.0,61.1,33.8,29.8,22.8,21.9,14.4,14.0.

[0252] 1 H NMR (400MHz, CDCl3) δ3.90 (s, 3H), 2.94-2.85 (m, 4H), 1.70-1.55 (m, 4H), 1.04-0.97 (m, 6H). 13 C NMR (100MHz, CDCl3) δ160.9,156.3,152.2,150.4,146.7,144.0,139.9,132.3,127.1,119 .9,119.5,115.4,110.9,60.8,33.6,29.9,23.0,22.1,14.2,13.9.HRMS(ESI)calcd.for[C 20 H 18 Cl4O5+Na] + 500.9806, found 500.9808.

[0253] Example 2: Antibacterial activity results of aryl ether compounds

[0254] 1. Antibacterial activity test (taking Candida albicans or Cryptococcus neoformans as examples)

[0255] Experimental bacterial strains: Methicillin-resistant Staphylococcus aureus (MRSA, ATCC43300) and Escherichia coli (E. coli, ATCC 25922). The bacterial strains were cryopreserved in tryptone soybean broth or agar (Tryptic Soy broth, TSB; Tryptic Soy Agar, TSA; BD Biosciences, San Jose, CA, USA). Fungi: Candida albicans (ATCC 10231) and Cryptococcus neoformans (ATCC66031). *C. albicans* was inoculated on YM liquid medium (Yeast malt, YM; Yeast malt agar, YMA; BD Biosciences, San Jose, CA, USA), and *C. neoformans* was inoculated on Sabouraud dextrose broth medium (Sabouraud dextrose broth, SDB; Sabouraud dextrose agar, SDA; BD Biosciences, San Jose, CA, USA). All strains were inoculated on their respective liquid media and stored at -80°C for later use. Before each experiment, the strains were re-inoculated onto solid agar plates and passaged at least twice to revive the strains.

[0256] Experimental instruments and consumables: Microbial constant temperature incubator (IRM, Germany), ultra-low temperature freezer (-80℃, Panasonic, Japan), clean bench (ESCO, ESCO Singapore), benchtop constant temperature shaker (HNY-1008, Tianjin Ounuo Instrument Co., Ltd.), Eppendorf benchtop centrifuge (Eppendorf, Germany), Epoch microplate spectrophotometer (Biotech, USA), bacterial culture plates (Guangzhou Jete Biotechnology Co., Ltd.).

[0257] Reagents: Tryptic Soy Broth or Agar (TSB; Tryptic Soy Agar; BD Biosciences, San Jose, CA, USA), YM Liquid Medium (Yeast Malt, YM; Yeast Maltagar, YMA; BD Biosciences, San Jose, CA, USA), and Sabouraud Dextrose Broth (SDB; Sabouraud Dextrose Agar, SDA; BD Biosciences, San Jose, CA, USA).

[0258] Experimental Method: Several monoclonal colonies of *Candida albicans* or *Cryptococcus neoformans* were picked from agar plates using a looper and inoculated into sterile broth. The colonies were activated by incubation overnight at 30°C and 200 rpm. The logarithmic growth phase colonies were then diluted to an OD600 value between 0.03 and 0.06. 195 μL of the diluted colonies were added to each well of a 96-well plate, followed by 5 μL of the drug. The plates were incubated for 24 hours (48 hours for *Cryptococcus neoformans*) and the OD600 value was measured.

[0259]

[0260] Table 1. Results of antibacterial activity tests of the compounds (concentration: 50 μg / mL) a

[0261]

[0262] a The activity test is the average of three experimental results.

[0263] Experimental Results and Discussion: The compounds of this invention exhibit varying degrees of inhibitory activity against both bacteria and fungi. Regarding antibacterial activity, compounds 2 and 13 showed moderate inhibitory activity against *Escherichia coli*. Compounds 8, 10, and 11 showed moderate inhibitory activity against methicillin-resistant *Staphylococcus aureus* (MRSA), while compounds 3, 6, 9, 13, and 24-29 showed strong inhibitory activity against MRSA. This indicates that the more chlorine atoms simultaneously substituted on both sides of the aromatic ring, the more beneficial the inhibitory effect against this bacterium.

[0264] Regarding antifungal activity, compounds 1-3 exhibited moderate inhibitory activity against *Candida albicans*, while compound 13 showed strong inhibitory activity. This indicates that substitution at the 3-position of the benzene ring with a methoxy group, chlorine atoms at positions 2 and 4, and a hydroxyl group at position 5 is beneficial for the inhibitory activity against this fungus. Compounds 2, 5, 6, 9, 12, and 24 showed moderate inhibitory activity against *Cryptococcus neoformans*, while compounds 1, 3, 10, and 13 showed strong inhibitory activity against *Cryptococcus neoformans*. This suggests that substitution at the 3-position of the benzene ring with a methoxy group, chlorine atoms at positions 2 and 4, and a hydroxyl group at position 5 is also beneficial for the inhibitory activity against this fungus. Overall, compound 13 exhibits a broader antibacterial spectrum.

[0265] Example 3: Antitumor activity test of the compound (using human lung cancer A549 cells as an example)

[0266] Experimental methods: The compound sample was dissolved in DMSO, and the cells were cultured in RPMI 1640 medium. Human lung cancer A549 tumor cells were cultured at 2-7 × 10⁻⁶. 4 Cells were seeded at a concentration of [cell / mL] in 96-well plates and cultured at 37°C and 5% CO2 for 24 h. 10 μL of the compound sample diluted with culture medium was added, resulting in a final concentration of 20 μg / mL per well. Three replicates were set up for each compound. The control group cells were replaced with DMSO. Three wells containing only culture medium and no cells served as background controls. After culturing for another 72 h, cells were fixed with 50% cold trichloroacetic acid solution and incubated at 4°C for 1 h. The fixative was washed off, and the cells were air-dried. 100 μL of 1% glacial acetic acid solution containing 0.4% SRB was added, and staining was performed for 15 min. Excess staining agent was washed off with 1% glacial acetic acid, and the cells were air-dried. 100 μL of 10 mM Tris buffer was added to dissolve the stain, and the absorbance (A) was read at 515 nm using a microplate reader.

[0267] Cell inhibition rate (%) = (average A value of control wells without drug - average A value of drug-treated wells) / average A value of control wells without drug × 100%.

[0268] After initial and secondary screening, the compounds were finally added to cultured cells at five different concentration gradients to repeat the tumor cell inhibitory activity assay. The percentage inhibition rate at each concentration was measured, and the half-maximal inhibitory concentration (IC50) was calculated using the Bliss program. 50 ).

[0269] Table 2. Inhibitory effect of compounds on A549 tumor cells (IC50) 50 (μM) a

[0270]

[0271] a The activity test results were obtained by averaging the results of three experiments.

[0272] Experimental Results and Discussion: Compounds 8, 11, 13, 24, 27, and 29 exhibited different degrees of anticancer activity, with compound 8 showing the best activity. This suggests that the presence of diphenyl ethers at positions 3 and 5 in this type of compound is beneficial for its antitumor activity.

Claims

1. Aryl ether compounds represented by formulas I-IV, or pharmaceutically acceptable salts thereof: in, R1 can be a halogen, OH, trifluoromethanesulfonic acid group, cyano, benzyloxy, C1-C6 alkyl, C1-C6 alkoxy, or C2-C6 alkenyl. R2 is H, halogen, C1-C6 alkyl, or C1-C6 alkoxy; R3 is H, benzyl, C1-C6 alkyl, or C1-C6 alkoxy; R4 is H, halogen, C1-C6 alkyl, or C1-C6 alkoxy; R5 is H, a halogen; R6 is a C1-C6 alkyl or C1-C6 alkoxy group; R7 is H, halogen, C1-C6 alkyl, or C1-C6 alkoxy; R8 can be OH, trifluoromethanesulfonic acid group, C2-C6 alkenyl group, benzyloxy group, C1-C6 alkyl group, or C1-C6 alkoxy group; R9 can be H, OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, or phenoxy. R 10 It can be H, benzyl, C1-C6 alkyl, or C1-C6 alkoxy. R 11 H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 12 The derivatives are H, benzyl, tert-butyldimethylsilyl, C1-C6 alkyl, and C1-C6 alkoxy. R 13 H, halogen; R 14 It can be H, benzyl, C1-C6 alkyl, or C1-C6 alkoxy. R 15 H, halogen, C1-C6 alkyl, C1-C6 alkoxy; n is 0-10, preferably 0-5, and more preferably 0-2; R 16 It can be halogen, OH, benzyloxy, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 alkenyl. R 17 H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 18 It can be H, benzyl, C1-C6 alkyl, or C1-C6 alkoxy. R 19 H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 20 H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 21 H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 22 The derivatives are H, benzyl, tert-butyldimethylsilyl, C1-C6 alkyl, and C1-C6 alkoxy. R 23 H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 24 The radicals are halogen, OH, amino, cyano, benzyloxy, phenoxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, and methyl methylene ether. R 25 The radicals are H, OH, benzyl, C1-C6 alkyl, and C1-C6 alkoxy. R 26 The components are H, OH, halogen, benzyloxy, C1-C6 alkyl, and C1-C6 alkoxy. R 27 H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 28 The derivatives are H, CH2OCH3, C1-C6 alkyl, benzyl, and C1-C6 alkoxy. R 29 H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 30 H, halogen, OH, methyl methylene ether, benzyloxy, C1-C6 alkyl, C1-C6 alkoxy, dimethyl tert-butyl silyl ether; R 31 The radicals are H, COR, OH, halogen, amino, cyano, benzyloxy, phenoxy, C1-C6 alkyl, C1-C6 alkoxy, and C2-C6 alkenyl. R = H, OH, C1-C6 alkoxy, benzyloxy.

2. The aryl ether compound of claim 1, or a pharmaceutically acceptable salt thereof. in, R1 can be a halogen, OH, trifluoromethanesulfonic acid group, cyano, benzyloxy, C1-C4 alkyl, C1-C4 alkoxy, or C2-C4 alkenyl. R2 is H, Cl, C1-C4 alkyl, or C1-C4 alkoxy; R3 is H, benzyl, C1-C4 alkyl, or C1-C4 alkoxy; R4 is H, Cl, C1-C4 alkyl, or C1-C4 alkoxy; R5 represents H and Cl; R6 is a C1-C4 alkyl or C1-C4 alkoxy group; R7 is H, Cl, C1-C4 alkyl, or C1-C4 alkoxy; R8 can be OH, trifluoromethanesulfonic acid group, C2-C4 alkenyl group, benzyloxy group, C1-C4 alkyl group, or C1-C4 alkoxy group. R9 can be H, OH, halogen, C1-C4 alkyl, C1-C4 alkoxy, benzyloxy, or phenoxy. R 10 It can be H, benzyl, C1-C4 alkyl, or C1-C4 alkoxy. R 11 H, halogen, C1-C4 alkyl, C1-C4 alkoxy; R 12 The derivatives are H, benzyl, tert-butyldimethylsilyl, C1-C4 alkyl, and C1-C4 alkoxy. R 13 H, halogen; R 14 It can be H, benzyl, C1-C4 alkyl, or C1-C4 alkoxy. R 15 H, halogen, C1-C4 alkyl, C1-C4 alkoxy; R 16 It can be halogen, OH, benzyloxy, C1-C4 alkyl, C1-C4 alkoxy, or C3-C6 alkenyl. R 17 H, halogen, C1-C4 alkyl, C1-C4 alkoxy; R 18 It can be H, benzyl, C1-C4 alkyl, or C1-C4 alkoxy. R 19 H, halogen, C1-C4 alkyl, C1-C4 alkoxy; R 20 H, halogen, C1-C4 alkyl, C1-C4 alkoxy; R 21 H, halogen, C1-C4 alkyl, C1-C4 alkoxy; R 22 The derivatives are H, benzyl, tert-butyldimethylsilyl, C1-C4 alkyl, and C1-C4 alkoxy. R 23 H, halogen, C1-C4 alkyl, C1-C4 alkoxy; R 24 The radicals are halogen, OH, amino, cyano, benzyloxy, phenoxy, C1-C4 alkyl, C1-C4 alkoxy, C2-C6 alkenyl, and methyl methylene ether. R 25 The radicals are H, OH, benzyl, C1-C4 alkyl, and C1-C4 alkoxy. R 26 It can be H, OH, F, benzyloxy, C1-C4 alkyl, or C1-C4 alkoxy. R 27 It can be H, Cl, C1-C4 alkyl, or C1-C4 alkoxy. R 28 The derivatives are H, CH2OCH3, C1-C4 alkyl, benzyl, and C1-C4 alkoxy. R 29 It can be H, Cl, C1-C4 alkyl, or C1-C4 alkoxy. R 30 It can be H, F, I, OH, methyl methylene ether, benzyloxy, C1-C4 alkyl, C1-C4 alkoxy, or dimethyl tert-butyl silyl ether; R 31 The radicals are H, COR, OH, halogen, amino, cyano, benzyloxy, phenoxy, C1-C4 alkyl, C1-C4 alkoxy, and C2-C6 alkenyl. R = H, OH, C1-C4 alkoxy, benzyloxy.

3. The aryl ether compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

4. An intermediate for preparing the aryl ether compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof:

5. A method for preparing aryl ether compounds of general formulas I-IV according to claims 1, characterized in that, Aromatic compounds containing carboxylic acids and aromatic compounds containing alcohols are used to prepare compounds of general formula II by the action of dicyclohexylcarbodiimide and 4-dimethylaminopyridine. Compounds of general formula II first undergo deprotection reaction, and then undergo cyclization under the catalysis of copper or palladium salts to form compounds with a seven-membered lactone ring. Further modification and derivatization of the seven-membered lactone ring compound yields compounds of general formula I. Compounds of general formula III are prepared by reacting aryl halides with phenolic compounds under the catalysis of copper or palladium salts. Compound IV was prepared by reacting phenolic compounds with haloalkanes under the action of an alkali.

6. The preparation method according to claim 5, characterized in that, Preparation process of compounds of general formula II: Preparation process of compounds of general formula I: Preparation process of compounds of general formula III: Preparation process of compounds of general formula IV: Among them, R1-R 31 As described in claim 1.

7. A pharmaceutical composition comprising an aryl ether compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof.

8. The use of any aryl ether compound of claims 1-3 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 7 in the preparation of an antibacterial drug, wherein the antibacterial drug is preferably an antifungal drug or an antibacterial drug.

9. The use of any aryl ether compound of claims 1-3 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 7 in the preparation of an antitumor drug, wherein the tumor is preferably lung cancer.

10. Use of the intermediate of claim 4 in the preparation of aryl ether compounds or pharmaceutically acceptable salts thereof.

Images