A novel barbanic acid ether derivative, its synthesis method and application

Abstract

The present invention discloses a novel ether derivative of epilichexol and its synthesis method and application. The new synthesis method uses oak moss (methyl 2,4-dihydroxybenzoate) as the starting material for compound synthesis to synthesize epilichexol and its derivatives. In this method, the corresponding intermediate phenol or acid is first synthesized, and finally the phenolic acid compounds are synthesized by esterification condensation, and finally the ether compounds are synthesized, effectively avoiding the unstable factors directly derived on the basis of esters, which is efficient and convenient and is an effective way suitable for the synthesis of phenolic acid compounds. Through the MTT method for detecting cytotoxicity experiments, these ether compounds are all toxic to MDCK cells and have cytotoxicity to cancer cells A549, HePG2 and 22RV1, indicating potential anti-tumor activity, which is of great significance for the treatment of anti-tumor diseases.

Description

Technical Field

[0001] The present invention relates to the technical field of compound synthesis and uses, and particularly relates to a novel ether derivative of embatic acid and its synthesis method and application. Background Art

[0002] Diphenyl ethers are a class of organic compounds with two aromatic rings and a flexible oxygen bridge, and are widely used in medicine and pesticides [1] and other fields. For example, sorafenib is a highly effective small molecule anti-cancer inhibitor for the treatment of advanced renal cancer [2] . Nimesulide is a non-steroidal anti-inflammatory drug that has been popular for decades. Diphenoconazole and famoxadone are used as fungicides to protect various plants such as rice, cotton and cereals from diseases [3,4] . Generally, diphenyl ethers are mainly formed by coupling phenols and aryl halides under the action of a catalyst to form a C-O bond. These methods have certain defects, such as requiring high temperature, expensive catalysts, or toxic solvents [5-10] .

[0003] Depsides are dimers formed by an ester bond between two aromatic rings and are the main secondary metabolites of lichens

[11] . Research reports that depsides have good biological properties, such as anti-tumor, antioxidant, and antibacterial activities [12-14] . Embatic acid is a depside widely found in lichens

[15] and has various biological activities such as anti-cancer, insecticidal, diuretic, and inhibition of plant and algal growth [16-20] . However, little attention has been paid to the structural modification of embatic acid to develop potential anti-tumor drugs. Therefore, structural modification of embatic acid and screening for better anti-tumor activity are of positive and important significance for the creation of a class of anti-tumor drugs with independent intellectual property rights in China.

[0004] After long-term experiments by the research team of the present invention, a synthesis method of a novel ether derivative of embatic acid was finally provided. Using inexpensive and readily available oak moss (methyl 2,4-dihydroxybenzoate) as the starting material to synthesize embatic acid and its derivatives. In addition, considering that ester compounds are not very stable in nature and it is difficult to directly carry out structural modification based on embatic acid, phenolic and benzoic acid intermediates were first synthesized, and then esterification was used to synthesize depside compounds one by one. Finally, catalytic hydrogenation reduction was used to synthesize depside compounds. This method of first synthesizing intermediates and finally esterification condensation effectively avoids the unstable factors of direct derivation based on esters and is efficient and convenient. Summary of the Invention

[0005] The object of the present invention is to provide a novel ether derivative of embatic acid;

[0006] The object of the present invention is to provide a method for synthesizing novel ether derivatives of barbanic acid;

[0007] Another object of the present invention is to provide the use of ether derivatives 9a - 9k of barbanic acid in the preparation of anti - tumor drugs or preparations.

[0008] The present invention is achieved through the following technical solutions:

[0009] The novel ether derivatives of barbanic acid described in the present invention have the following general chemical formula:

[0010]

[0011] In the novel ether derivatives of barbanic acid described in the present invention, there is an - O - bond in the general chemical formula, and R 1 and R 2 include the following structures and are not limited to the following:

[0012]

[0013]

[0014] The method for synthesizing the novel ether derivatives of barbanic acid described in the present invention uses barbanic acid esters as raw materials and potassium hydroxide to mediate an intramolecular rearrangement reaction. The specific steps are as follows:

[0015] Weigh 1.2 mmol of KOH and measure 11 mL of DMSO aqueous solution with a measuring cylinder and add them into a clean 100 - mL round - bottom flask equipped with a magnetic stirrer. After the KOH is completely dissolved, add 1 mmol of the corresponding barbanic acid ester derivative. Fix the reaction system on a thermostatic magnetic stirrer with an iron stand and iron clamp and react at room temperature. After TLC detection every 30 min until the reaction is complete, slowly add 1 M hydrochloric acid to adjust the pH to 1 - 2. Solid powder precipitates, filter by suction, and dry in an oven to obtain the pure product of the target compound 9a - 9k.

[0016] The rearrangement reaction synthesis route diagram of the above - mentioned target compound 9a - 9k is as follows:

[0017]

[0018] The barbanic acid ester derivatives described in the present invention are obtained by using oak moss as a raw material, through substitution, hydrolysis, etc. to synthesize benzoic acid intermediates and phenolic intermediates, and then through an esterification reaction; specifically, it includes the following steps:

[0019] (I) Total synthesis of barbanic acid

[0020] (1) Synthesis of benzoic acid intermediates:

[0021] Synthesis of Intermediate 2a: Weigh oak moss (500 mg, 2.5 mmol) and anhydrous K2CO3 (691 mg, 5.0 mmol) and add them to a 100 mL round-bottom flask pre-equipped with a magnetic stir bar. Then, pipette 0.5 mL of dimethyl sulfate into it. Finally, measure 30 mL of acetone with a graduated cylinder and add it to the round-bottom flask containing the raw materials and catalyst. After that, fix the reaction system of the round-bottom flask on a thermostatic magnetic stirrer with an iron stand and an iron clamp for oil bath stirring and reflux. TLC detection (petroleum ether: ethyl acetate = 3:1) is carried out every half hour until the reaction is complete. Then, let it stand at room temperature, rotary evaporate the acetone completely, add 20 mL of water to remove the excess anhydrous K2CO3, and then extract with ethyl acetate three times, 30 mL each time. Combine the organic layers, dry them with anhydrous Na2SO4, filter, rotary evaporate, and purify the crude product by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 2a; the synthetic route is as follows:

[0022]

[0023] Synthesis of Intermediates 3a - 3f: Prepare a clean 100 mL round-bottom flask equipped with a magnetic stir bar in advance. Then, weigh KOH (673.3 mg, 12 mmol) with an analytical balance and measure ethanol: water = 25:1 (26 mL) with a graduated cylinder and add them to it. Finally, fix the round-bottom flask containing the solvent and KOH on a thermostatic magnetic stirrer with an iron stand and an iron clamp to completely dissolve it. Then, add the corresponding compound (687.2 mg, 2.4 mmol) and react at room temperature; TLC detection is carried out every half hour until the reaction is complete. After that, let it cool to room temperature, slowly add 1 M hydrochloric acid to adjust the pH to 1 - 2, and a solid powder will precipitate. Filter it by suction, and dry the powder in an oven (35 °C) to obtain compounds 3a - 3f; the synthetic route is as follows:

[0024]

[0025] (2) Synthesis of phenolic intermediates:

[0026] Synthesis of Compound 4: First, weigh 3b (381.2 mg, 1.4 mmol) and measure 25 mL of ethyl acetate and add them to a three-necked round-bottom flask equipped with a magnetic stir bar. Then, fill the flask with nitrogen to displace the air in the bottle, add 76 mg of 10% Pd / C, and then fill the bottle with hydrogen to displace the nitrogen. After that, fix the reaction system of the round-bottom flask on a thermostatic magnetic stirrer with an iron stand and an iron clamp, and react at room temperature under hydrogen protection. TLC detection (petroleum ether: ethyl acetate = 5:1) is carried out every half hour until the reaction is complete. Then, stop filling the hydrogen, exhaust the air in the bottle with nitrogen, and then open the flask to take out the magnetic stir bar; after filtering the mixed liquid, concentrate it and purify it by recrystallization with petroleum ether to obtain compound 4. (Note: After the reaction, put the used Pd / C into a pre-prepared water recovery bottle to prevent spontaneous combustion), the synthetic route is as follows:

[0027]

[0028] Synthesis of Compound 5a: Weigh compound 4 (500 mg, 2.74 mmol) and KHCO3 (411.45 mg, 4.11 mmol) with an analytical balance and add them to a 50 mL round-bottom flask equipped with a magnetic stir bar. Then, measure 10 mL of DMF with a measuring cylinder and pipette the corresponding bromide (3.3 mmol) into it. After the addition, fix the reaction system of the round-bottom flask on a thermostatic magnetic stirrer with an iron stand and iron clamp and react at room temperature. TLC detection is carried out every half hour until the reaction is complete. Then, add 20 mL of water, and slowly add 1 M hydrochloric acid to adjust the pH to 3 - 4 until a solid precipitates. Filter by suction and dry in an oven (35 °C) to obtain compound 5a. The synthetic route is as follows:

[0029]

[0030] (3) Condensation reaction:

[0031] Synthesis of Compound 6a: Weigh 3a (1.1 mmol) and 5a with an analytical balance and add them to a 50 mL round-bottom flask equipped with a magnetic stir bar. Measure 20 mL of dichloromethane with a measuring cylinder and pipette 0.31 mL of trifluoroacetic anhydride into it. After the addition, fix the reaction system of the round-bottom flask on a thermostatic magnetic stirrer with an iron stand and iron clamp and react at room temperature. TLC detection is carried out every half hour until the reaction is complete. Then, add 10 mL of water and extract with dichloromethane twice, 30 mL each time. Combine the organic layers, dry over anhydrous Na2SO4, filter, evaporate to dryness, and purify the crude product by column chromatography to obtain compound 6a. The synthetic route is as follows:

[0032]

[0033] (II) Synthesis of barbanic acid derivatives

[0034] (1) Synthesis of benzoic acid intermediates:

[0035] Synthesis of Intermediate 2b: Weigh evernia prunastri (500 mg, 2.5 mmol) and anhydrous K2CO3 (691 mg, 5.0 mmol), and add them into a 100 mL round-bottom flask pre-equipped with a magnetic stir bar. Then, pipette 0.4 mL of BnBr into the flask. Finally, measure 30 mL of acetone with a graduated cylinder and add it to the round-bottom flask containing the raw materials and catalyst. After that, fix the reaction system of the round-bottom flask on an oil bath of a thermostatic magnetic stirrer with an iron stand and an iron clamp for stirring and refluxing. TLC detection (petroleum ether: ethyl acetate = 3:1) is carried out every half hour until the reaction is complete. Then, let it cool to room temperature, rotary evaporate the acetone until dry, add 20 mL of water to remove the excess anhydrous K2CO3, and then extract with ethyl acetate three times, 30 mL each time. Combine the organic layers, dry them with anhydrous Na2SO4, filter, rotary evaporate to dryness, and purify the crude product by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 2b. The synthetic route is as follows:

[0036]

[0037] Synthesis of Intermediates 2c - 2f: Weigh evernia prunastri (300 mg, 1.5 mmol) and anhydrous K2CO3 (310.95 mg, 2.25 mmol) with an analytical balance and add them into a 25 mL round-bottom flask equipped with a magnetic stir bar. Then, pipette the bromides (ethyl bromide, propyl bromide, isopropyl bromide, allyl bromide) (1.5 mmol) into the flask. Finally, measure 5 mL of DMF with a graduated cylinder and add it to the round-bottom flask containing the raw materials and catalyst. Thereafter, fix the reaction system of the round-bottom flask on an oil bath of a thermostatic magnetic stirrer with an iron stand and an iron clamp for stirring and refluxing. TLC detection is carried out every half hour until the reaction is complete. Then, let it cool to room temperature, slowly add 1 M hydrochloric acid dropwise to adjust the pH to 1 - 2, add 10 mL of water, and then extract with ethyl acetate three times, 30 mL each time. Combine the organic layers, dry them with anhydrous Na2SO4, filter, rotary evaporate to dryness, and purify the crude product by column chromatography to obtain compounds 2c - 2f. The synthetic route is as follows:

[0038]

[0039] Synthesis of Intermediates 3c - 3f: Prepare a clean 100 mL round-bottom flask equipped with a magnetic stir bar in advance. Then, weigh KOH (673.3 mg, 12 mmol) with an analytical balance and measure ethanol: water = 25:1 (26 mL) with a graduated cylinder and add them into the flask. Finally, fix the round-bottom flask containing the solvent and KOH on a thermostatic magnetic stirrer with an iron stand and an iron clamp to completely dissolve it. Then, add the corresponding compound (687.2 mg, 2.4 mmol) and react at room temperature. TLC detection is carried out every half hour until the reaction is complete. Then, let it cool to room temperature, slowly add 1 M hydrochloric acid dropwise to adjust the pH to 1 - 2, and a solid powder will precipitate. Filter it by suction, and dry the powder in an oven (35 °C) to obtain compounds 3c - 3f. The synthetic route is as follows:

[0040]

[0041] (2) Synthesis of phenolic intermediates:

[0042] Synthesis of compounds 5b - 5f: Weigh compound 4 (500 mg, 2.74 mmol) and KHCO3 (411.45 mg, 4.11 mmol) using an analytical balance and add them to a pre-prepared 50 mL round-bottom flask equipped with a magnetic stir bar. Then, measure 10 mL of DMF using a graduated cylinder and pipette the corresponding bromide (ethyl bromide, propyl bromide, isopropyl bromide, allyl bromide, cyanogen bromide) (3.3 mmol) into it. After the addition, fix the reaction system of the round-bottom flask on a thermostatic magnetic stirrer with an iron stand and iron clamp and react at room temperature. Every half an hour, monitor the reaction by TLC until it is complete. Then, add 20 mL of water, and slowly add 1 M hydrochloric acid to adjust the pH to 3 - 4 until a solid precipitates. Filter by suction and dry in an oven (35 °C) to obtain compounds 5b - 5f; the synthetic route diagram is as follows:

[0043]

[0044] (3) Synthesis of derivatives:

[0045] Synthesis of compounds 6b - 6p′: Weigh the corresponding benzoic acid intermediate (1.1 mmol) and the corresponding phenol (1.1 mmol) using an analytical balance and add them to a 50 mL round-bottom flask equipped with a magnetic stir bar. Measure 20 mL of dichloromethane using a graduated cylinder and pipette 0.31 mL of trifluoroacetic anhydride into it. After the addition, fix the reaction system of the round-bottom flask on a thermostatic magnetic stirrer with an iron stand and iron clamp and react at room temperature. Every half an hour, monitor the reaction by TLC until it is complete. Then, add 10 mL of water and extract twice with dichloromethane, 30 mL each time. Combine the organic layers, dry over anhydrous Na2SO4, filter, rotary evaporate, and purify the crude product by column chromatography to obtain compounds 6b - 6p′; the synthetic route diagram is as follows:

[0046]

[0047] The volume ratio of the DMSO aqueous solution described in the present invention is: DMSO: water = 10:1.

[0048] The reagent for TLC detection described in the present invention is: petroleum ether: ethyl acetate = 3:1.

[0049] The drying temperature in the oven described in the present invention is 35 °C.

[0050] Application of the ether compounds 9a - 9k obtained by the synthetic method of the novel barbasal acid ether compounds described in the present invention in the preparation of drugs or preparations for inhibiting the proliferation of MDCK cells.

[0051] The preparation of the present invention is prepared into a pharmaceutically acceptable preparation by adding pharmaceutically acceptable excipients, and the pharmaceutically acceptable preparation is a solid preparation or a liquid preparation.

[0052] The solid preparations of the present invention are granules, capsules, tablets, pills; the liquid preparations are injection preparations and oral liquids.

[0053] Advantages of the present invention:

[0054] 1. Using evernia prunastri as a raw material, phenolic and benzoic acid intermediates are first synthesized, and then an esterification condensation method is adopted. With DMSO: water = 10:1 as the solvent and KOH catalysis, the ester bond at the corresponding intermediate position of the depside acid will break, and the depside acid compound will rearrange to form the corresponding ether. This reaction is a new synthetic route for depside ethers. Finally, 11 ether compounds 9a - 9k are synthesized, all of which are synthesized for the first time.

[0055] 2. The raw material evernia prunastri selected in the present invention is inexpensive and easily available; first synthesizing phenolic and benzoic acid intermediates, and then adopting the esterification condensation method effectively avoids the unstable factors directly derived on the basis of esters, which is efficient and convenient, and is an effective way suitable for the synthesis of depside acid compounds.

[0056] 3. In the key step of phenolic acid condensation in the present invention, trifluoroacetic anhydride is selected. It has two strong electron-withdrawing groups (trifluoromethyl), and is a relatively strong organic acid anhydride with active properties. In the esterification reaction, it reacts with carboxylic acid to form the corresponding mixed acid anhydride (i.e., activated ester), enhancing the electrophilicity of the carboxylic acid carbonyl, effectively reducing the steric hindrance, and enabling the reaction to proceed, solving the problem that the steric hindrance of such compounds increases due to the presence of more groups, resulting in difficult condensation reactions.

[0057] 4. Through the MTT cell toxicity experiment of the present invention, the results show that at a concentration of 100 μmol / mL, the ester derivatives are basically non-toxic to MDCK cells, while the ether compounds (9a - 9k) are all highly toxic to MDCK cells. Except for 9a (-3.02) and 9b (-2.53), the remaining ether compounds all have significant toxicity (P < 0.05); indicating that the ether compounds (9a - 9k) have a certain inhibitory effect on MDCK cells and can be used in the preparation of drugs or preparations for inhibiting the proliferation of MDCK cells.

[0058] 5. The growth inhibitory activity of the target compounds 9a-9k against three cancer cells (A549, HepG2, and 22RV1) was determined by MTT assay. The results showed that the compounds 9a, 9c, 9e, and 9f prepared in the present invention had moderate cytotoxic activity against A549 cells, with half-inhibitory concentration values of 2.61, 1.43, and 2.21 mmol / L, respectively; the compounds 9a-d and 9i-j had high cytotoxic activity against HepG2 cells, with good activity and half-inhibitory concentration values of 0.41-1.56 mmol / L; the compound 9d had the best anti-proliferative activity against 22RV1 cells, with a half-inhibitory concentration value of 0.78 mmol / L. This indicates that the derivatives synthesized in the present invention have potential anti-tumor activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 : 1H NMR spectrum of compound 9a 1 1H NMR spectrum

[0060] Figure 2 : Compound 9a 13 13C NMR spectrum

[0061] Figure 3 : HRMS spectrum of compound 9a

[0062] Figure 4 : 1H NMR spectrum of compound 9b 1 1H NMR spectrum

[0063] Figure 5 : 1H NMR spectrum of compound 9b 13 13C NMR spectrum

[0064] Figure 6 : HRMS spectrum of compound 9b

[0065] Figure 7 : 1H NMR spectrum of compound 9c 1 1H NMR spectrum

[0066] Figure 8 : 1H NMR spectrum of compound 9c 13 13C NMR spectrum

[0067] Figure 9 : HRMS spectrum of compound 9c

[0068] Figure 10 : 1H NMR spectrum of compound 9d 1 1H NMR spectrum

[0069] Figure 11 : 1H NMR spectrum of compound 9d 13 13C NMR spectrum

[0070] Figure 12: HRMS spectrum of compound 9d

[0071] Figure 13 : of compound 9e 1 H NMR spectrum

[0072] Figure 14 : of compound 9e 13 C NMR spectrum

[0073] Figure 15 : HRMS spectrum of compound 9e

[0074] Figure 16 : of compound 9f 1 H NMR spectrum

[0075] Figure 17 : of compound 9f 13 C NMR spectrum

[0076] Figure 18 : HRMS spectrum of compound 9f

[0077] Figure 19 : of compound 9g 1 H NMR spectrum

[0078] Figure 20 : of compound 9g 13 C NMR spectrum

[0079] Figure 21 : HRMS spectrum of compound 9g

[0080] Figure 22 : of compound 9h 1 H NMR spectrum

[0081] Figure 23 : of compound 9h 13 C NMR spectrum

[0082] Figure 24 : HRMS spectrum of compound 9h

[0083] Figure 25 : of compound 9i 1 H NMR spectrum

[0084] Figure 26 : of compound 9i 13 C NMR spectrum

[0085] Figure 27 : HRMS spectrum of compound 9i

[0086] Figure 28 : of compound 9j 1 H NMR spectrum

[0087] Figure 29 : 13C NMR spectrum of compound 9j 13 13C NMR spectrum

[0088] Figure 30 : HRMS spectrum of compound 9j

[0089] Figure 31 : 1H NMR spectrum of compound 9k 1 1H NMR spectrum

[0090] Figure 32 : 13C NMR spectrum of compound 9k 13 13C NMR spectrum

[0091] Figure 33 : HRMS spectrum of compound 9k

[0092] Figure 34 : X-ray single crystal diffraction - derivative 9a

[0093] Figure 35 : MTT assay of the cytotoxicity of compounds 9a - 9k against MDCK cells Detailed implementation manners

[0094] The technical solutions of the present invention will be further specifically described below through specific embodiments.

[0095] Example 1 Synthesis of novel barbanic acid ether compounds (9a - 9k)

[0096] (I) Total synthesis of barbanic acid

[0097] (1) Synthesis of benzoic acid intermediates:

[0098] Synthesis of intermediate 2a: Weigh 500 mg (2.5 mmol) of oak moss and 691 mg (5.0 mmol) of anhydrous K2CO3, and add them to a 100 mL round-bottom flask pre-loaded with a magnetic stir bar. Then, pipette 0.5 mL of dimethyl sulfate into it, and finally measure 30 mL of acetone with a graduated cylinder and add it to the round-bottom flask containing the raw materials and catalyst. After that, fix the reaction system of the round-bottom flask on a thermostatic magnetic stirrer with an iron stand and an iron clamp for oil bath stirring and reflux. TLC detection (petroleum ether: ethyl acetate = 3:1) is carried out every half hour until the reaction is complete. Then, let it cool to room temperature, rotary evaporate the acetone, add 20 mL of water to remove the excess anhydrous K2CO3, and then extract with ethyl acetate three times, 30 mL each time. Combine the organic layers, dry them with anhydrous Na2SO4, filter, rotary evaporate, and purify the crude product by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 2a; the synthetic route diagram is as follows:

[0099]

[0100] The physical properties and spectral analysis of compound 2a are as follows:

[0101]

[0102] Compound 2a: Yield = 97.3%, white solid, mp 103 - 106 °C; 1 H NMR(400MHz,CDCl3)δ11.82(s,1H,OH),6.27(s,1H,H - Ar),3.92(s,3H,OCH3),3.85(s,3H,OCH3),2.52(s,3H,CH3),2.07(s,3H,CH3). 13 C NMR(100MHz,CDCl3)δ170.36,159.89,159.18,137.92,108.63,103.64,103.25,75.14,74.82,74.50,53.24,49.58,22.45,5.59.MS(ESI)m / z:211.10[M + H] + .

[0103] Synthesis of intermediates 3a - 3f: Prepare a clean 100 mL round - bottom flask equipped with a magnetic stir bar in advance. Then, weigh KOH (673.3 mg, 12 mmol) using an analytical balance and measure ethanol:water = 25:1 (26 mL) using a graduated cylinder and add them into the flask. Finally, fix the round - bottom flask containing the solvent and KOH on a thermostatic magnetic stirrer with an iron stand and clamp to completely dissolve it. Then add the corresponding compound (687.2 mg, 2.4 mmol) and react at room temperature; perform TLC detection every half an hour until the reaction is complete, then let it cool to room temperature, slowly add 1 M hydrochloric acid to adjust the pH to 1 - 2, precipitate the solid powder, filter it by suction, and dry the powder in an oven (35 °C) to obtain compounds 3a - 3f; the synthetic route diagram is as follows:

[0104]

[0105] The physical properties and spectral analysis of compounds 3a - 3b are as follows:

[0106]

[0107] Compound 3a: Yield = 96.7%, white solid, mp > 320 °C; 1 H NMR(400MHz,DMSO - d6)δ6.46(s,1H,H - Ar),3.83(s,3H,OCH3),2.51(S,3H,CH3),1.96(s,3H,CH3). 1313C NMR (100 MHz, DMSO-d6) δ 174.19, 161.91, 161.01, 140.53, 109.47, 106.12, 105.63, 55.75, 24.22, 8.09. MS (ESI) m / z: 197.10 [M+H] + .

[0108]

[0109] Compound 3b: Yield = 69.7%, white solid, mp 200 - 203 °C; 1 1H NMR (400 MHz, DMSO-d6) δ 7.48–7.30 (m, 5H, H-Ar), 6.57 (s, 1H, H-Ar), 5.18 (s, 2H, CH2), 2.48 (s, 3H, CH3), 2.01 (s, 3H, CH3). 13 13C NMR (100 MHz, CDCl3) δ 179.11, 167.02, 165.11, 145.35, 142.20, 133.71, 133.05, 132.55, 114.98, 112.40, 110.86, 74.50, 29.20, 13.27. MS (ESI) m / z: 273.10 [M+H] + .

[0110] (2) Synthesis of phenolic intermediates:

[0111] Synthesis of Compound 4: First, weigh 3b (381.2 mg, 1.4 mmol) and measure 25 mL of ethyl acetate and put them into a three-necked round-bottom flask equipped with a magnetic stir bar. Then, purge the air in the flask with nitrogen, add 76 mg of 10% Pd / C, and then purge the nitrogen in the flask with hydrogen. After that, fix the round-bottom flask reaction system on a thermostatic magnetic stirrer with an iron stand and an iron clamp, and react at room temperature under hydrogen protection. TLC detection (petroleum ether:ethyl acetate = 5:1) is carried out every half hour until the reaction is complete. Then, stop introducing hydrogen, purge the air in the flask with nitrogen, and then open the flask to take out the magnetic stir bar. The mixed liquid is filtered, concentrated, and purified by recrystallization with petroleum ether to obtain Compound 4. (Note: The Pd / C after the reaction is put into a pre-prepared water-containing recovery bottle to prevent spontaneous combustion). The synthesis route diagram is as follows:

[0112]

[0113] The physical properties and spectral analysis of Compound 4 are as follows:

[0114]

[0115] Compound 4: Yield = 69.5%, white solid, mp 171 - 174 °C; 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H, OH), 6.25 (s, 1H, H-Ar), 2.39 (s, 3H, CH3), 1.93 (s, 3H, CH3). 13 C NMR (100 MHz, DMSO-d6) δ 173.92, 162.86, 159.73, 139.31, 110.08, 107.67, 103.32, 23.58, 7.75. MS(ESI) m / z: 182.10 [M + H] + .

[0116] Synthesis of Compound 5a: Weigh Compound 4 (500 mg, 2.74 mmol) and KHCO3 (411.45 mg, 4.11 mmol) using an analytical balance and add them to a pre-prepared 50 mL round-bottom flask equipped with a magnetic stir bar. Then, measure 10 mL of DMF using a graduated cylinder and pipette the corresponding bromide (3.3 mmol) into it. After the addition, fix the round-bottom flask reaction system on a thermostatic magnetic stirrer with an iron stand and iron clamp and react at room temperature. TLC was monitored every half hour until the reaction was complete. Then, add 20 mL of water, and slowly add 1 M hydrochloric acid to adjust the pH to 3 - 4 until a solid precipitated. Filter by suction and dry in an oven (35 °C) to obtain Compound 5a; its synthetic route is as follows:

[0117]

[0118] The physical properties and spectral analysis of Compound 5a are as follows:

[0119]

[0120] Compound 5a: Yield = 80.9%, white solid, mp 117 - 119 °C; 1 H NMR (400 MHz, CDCl3) δ 12.05 (s, 1H), 7.45–7.31 (m, 5H, H-Ar), 6.19 (s, 1H, H-Ar), 5.38 (s, 2H), 2.45 (s, 3H, CH3), 2.11 (s, 3H, CH3). 13 C NMR (100 MHz, CDCl3) δ 172.38, 163.76, 158.56, 140.74, 135.92, 129.10, 128.87, 111.08, 109.05, 105.61, 67.48, 24.88, 8.11. MS(ESI) m / z: 295.10 [M + Na] + .

[0121] (3) Condensation reaction:

[0122] Synthesis of compound 6a: Weigh 3a (1.1 mmol) and 5a with an analytical balance and add them to a 50 mL round-bottom flask equipped with a magnetic stir bar. Measure 20 mL of dichloromethane with a graduated cylinder and pipette 0.31 mL of trifluoroacetic anhydride into it. After the addition, fix the reaction system of the round-bottom flask on a thermostatic magnetic stirrer with an iron stand and clamp, and react at room temperature. TLC is used to detect every half hour until the reaction is complete. Then add 10 mL of water and extract twice with dichloromethane, 30 mL each time. Combine the organic layers, and finally dry with anhydrous Na2SO4, filter, rotary evaporate, and purify the crude product by column chromatography to obtain compound 6a; its synthetic route is as follows:

[0123]

[0124] The physical properties and spectral analysis of compound 6a are as follows:

[0125]

[0126] Compound 6a: Yield = 40%, white solid, mp 118 - 121 °C; 1 H NMR (400 MHz, CDCl3) δ 11.92 (s, 1H, OH), 11.51 (s, 1H, OH), 7.48–7.34 (m, 5H, H-Ar), 6.51 (s, 1H, H-Ar), 6.38 (s, 1H, H-Ar), 5.43 (s, 2H, CH2Ph), 3.90 (s, 3H, OCH3), 2.69 (s, 3H, CH3), 2.52 (s, 3H, CH3), 2.10 (s, 3H, CH3), 2.09 (s, 3H, CH3). 13 C NMR (100 MHz, CDCl3) δ 172.07, 170.65, 163.45, 162.70, 153.07, 141.19, 140.23, 135.54, 129.18, 129.05, 128.93, 117.48, 116.88, 111.75, 110.35, 106.88, 104.79, 67.94, 56.03, 25.54, 24.79, 9.79, 8.27. MS (ESI) m / z: 451.1 [M + H] + . HRMS (ESI) calcd for C 26 H 26 O7Na [M + Na] + : 473.1571, found 473.1571.

[0127] (4) Catalytic hydrogenation reaction:

[0128] Synthesis of compound 7: First, weigh 420 mg (0.93 mmol) of compound 6a and measure 25 mL of ethyl acetate, then put them into a three-necked round-bottom flask equipped with a magnetic stir bar. Then, purge the air in the flask with nitrogen, add 84 mg of 10% Pd / C, and then purge the nitrogen in the flask with hydrogen. After the treatment, fix the reaction system of the round-bottom flask on a thermostatic magnetic stirrer with an iron stand and an iron clamp, and react at room temperature under the protection of hydrogen. TLC detection (petroleum ether: ethyl acetate = 5:1) is carried out every half hour until the reaction is complete. Then, stop introducing hydrogen, purge the air in the flask with nitrogen, and then open the flask to take out the magnetic stir bar. The mixed liquid is filtered, concentrated, and recrystallized with petroleum ether to obtain compound 7; the synthetic route diagram is as follows:

[0129]

[0130] The physical properties and spectral analysis of compound 7 are as follows:

[0131]

[0132] Compound 7: Yield = 87.5%, white solid, mp 187 - 190 °C; 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 6.70 (s, 1H, H-Ar), 6.60 (s, 1H, H-Ar), 3.87 (s, 3H, OCH3), 2.57 (s, 3H, CH3), 2.49 (s, 3H, CH3), 2.01 (s, 3H, CH3), 2.01 (s, 3H, CH3). 13 C NMR (100 MHz, DMSO-d6) δ 173.21, 168.65, 161.32, 161.14, 159.51, 151.87, 139.03, 139.01, 116.06, 115.80, 111.38, 110.04, 107.00, 106.36, 55.77, 23.11, 22.84, 9.11, 8.07. MS (ESI) m / z: 337.1 [M + H] + . HRMS (ESI) calcd for C 19 H 20 O7Na [M + Na] + : 383.1101, found 383.1101.

[0133] (II) Synthesis of babaic acid derivatives

[0134] (1) Synthesis of benzoic acid intermediates:

[0135] Synthesis of Intermediate 2b: Weigh oak moss (500 mg, 2.5 mmol) and anhydrous K2CO3 (691 mg, 5.0 mmol) and add them to a 100 mL round-bottom flask pre-equipped with a magnetic stir bar. Then, pipette 0.4 mL of BnBr into it. Finally, measure 30 mL of acetone with a graduated cylinder and add it to the round-bottom flask containing the raw materials and catalyst. After that, fix the reaction system of the round-bottom flask on an oil bath magnetic stirrer with an iron stand and iron clamp for stirring and refluxing. TLC detection (petroleum ether: ethyl acetate = 3:1) is carried out every half hour until the reaction is complete. Then, let it stand at room temperature, rotary evaporate the acetone, add 20 mL of water to remove the excess anhydrous K2CO3, and then extract with ethyl acetate three times, 30 mL each time. Combine the organic layers, dry them with anhydrous Na2SO4, filter, rotary evaporate to dryness, and purify the crude product by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 2b. The synthetic route diagram is as follows:

[0136]

[0137] The physical properties and spectral analysis of compound 2b are as follows:

[0138]

[0139] Compound 2b: Yield = 95.3%, white solid, mp 76 - 79 °C; 1 H NMR (400 MHz, CDCl3) δ 11.86 (s, 1H, OH), 7.46 - 7.34 (m, 5H, H-Ar), 6.35 (s, 1H, H-Ar), 5.12 (s, 2H, CH2), 3.93 (s, 3H, OCH3), 2.52 (s, 3H, CH3), 2.16 (s, 3H, CH3). 13 C NMR (100 MHz, CDCl3) δ 172.53, 162.26, 160.57, 140.06, 136.85, 128.58 (2C), 127.93, 127.07 (2C), 111.39, 107.12, 105.68, 69.84, 51.81, 24.65, 8.08. MS (ESI) m / z: 287.10 [M + H] + .

[0140] Synthesis of intermediates 2c - 2f: Weigh evernia prunastri (300 mg, 1.5 mmol) and anhydrous K2CO3 (310.95 mg, 2.25 mmol) using an analytical balance and add them to a 25 mL round-bottom flask equipped with a magnetic stir bar. Then, pipette bromides (ethyl bromide, propyl bromide, isopropyl bromide, allyl bromide) (1.5 mmol) into it. Finally, measure 5 mL of DMF using a graduated cylinder and add it to the round-bottom flask containing the raw materials and catalyst. After that, fix the reaction system of the round-bottom flask on an oil bath magnetic stirrer with an iron stand and iron clamp for stirring and refluxing. Monitor the reaction by TLC every half hour until it is complete, then let it cool to room temperature. Slowly add 1 M hydrochloric acid to adjust the pH to 1 - 2, add 10 mL of water, and then extract with ethyl acetate three times, 30 mL each time. Combine the organic layers, dry over anhydrous Na2SO4, filter, and evaporate the solvent. The crude product is purified by column chromatography to obtain compounds 2c - 2f. The synthetic route is as follows:

[0141]

[0142] The physical properties and spectral analysis of compounds 2c - 2f are as follows:

[0143]

[0144] Compound 2c: Yield = 96.2%, white solid, mp 123 - 126 °C; 1 H NMR(400MHz,CDCl3)δ11.82(s,1H,OH),6.25(s,1H,H-Ar),4.07(q,J=7.0Hz,2H,CH2CH3),3.92(s,3H,OCH3),2.51(s,3H,CH3),2.08(s,3H,CH3),1.42(t,J=7.0Hz,3H,CH2CH3). 13 C NMR(100MHz,CDCl3)δ172.39,162.01,160.72,139.79,110.78,106.57,105.05,63.48,51.56,24.44,14.66,7.68.MS(ESI)m / z:225.10[M+H] + .

[0145]

[0146] Compound 2d: Yield = 73.8%, white solid, mp 76 - 79 °C; 11H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H, OH), 6.26 (s, 1H, H-Ar), 3.96 (t, J = 6.4 Hz, 2H, CH2), 3.92 (s, 3H, OCH3), 2.51 (s, 3H, CH3), 2.09 (s, 3H, CH3), 1.82 (m, 2H, CH2), 1.05 (t, J = 7.4 Hz, 3H, CH3). 13 13C NMR (100 MHz, CDCl3) δ 172.59, 162.18, 161.04, 139.99, 111.01, 106.79, 105.21, 69.58, 51.75, 24.63, 22.66, 10.58, 7.82. MS (ESI) m / z: 261.10 [M+Na] + .

[0147]

[0148] Compound 2e: Yield = 85.2%, white solid, mp 62 - 65 °C; 1 1H NMR (400 MHz, CDCl3) δ 11.84 (s, 1H, OH), 6.27 (s, 1H, H-Ar), 4.64–4.56 (m, 1H, CH), 3.92 (s, 3H, CH3), 2.50 (s, 3H, CH3), 2.06 (s, 3H, CH3), 1.35 (s, 3H, CH3), 1.33 (s, 3H, CH3). 13 13C NMR (100 MHz, CDCl3) δ 172.57, 162.50, 160.14, 139.70, 112.03, 108.19, 105.02, 70.21, 51.74, 24.65, 22.28, 8.07. MS (ESI) m / z: 239.10 [M+H] + .

[0149] Compound 2f: Yield = 71.1%, white solid, mp 60 - 62 °C; 1 1H NMR (400 MHz, CDCl3) δ 11.83 (s, 1H, OH), 6.25 (s, 1H, H-Ar), 6.02 (s, 1H, CHCH2), 5.45 (s, 1H CHCH2), 5.27 (s, 1H, OCH2), 4.59 (s, 2H), 3.92 (s, 3H, OCH3), 2.51 (s, 3H, CH3), 2.11 (s, 3H, CH3). 1313C NMR (100 MHz, CDCl3) δ 172.99, 162.70, 160.87, 140.42, 133.46, 117.73, 111.68, 107.42, 105.98, 69.12, 52.23, 25.08, 8.38. MS (ESI) m / z: 237.10 [M+H] + .

[0150] Synthesis of intermediates 3c - 3f: Prepare a clean 100 mL round-bottom flask equipped with a magnetic stir bar in advance. Then, weigh KOH (673.3 mg, 12 mmol) using an analytical balance and measure ethanol:water = 25:1 (26 mL) using a graduated cylinder, and add them into the flask. Finally, fix the round-bottom flask containing the solvent and KOH on a thermostatic magnetic stirrer with an iron stand and clamp to completely dissolve it. Then add the corresponding compound (687.2 mg, 2.4 mmol) and react at room temperature. Monitor the reaction by TLC every half hour until it is complete, then let it cool to room temperature. Slowly add 1 M hydrochloric acid to adjust the pH to 1 - 2, and a solid powder will precipitate. Filter it by suction, and dry the powder in an oven (35 °C) to obtain compounds 3c - 3f. The synthetic route is as follows:

[0151]

[0152] The physical properties and spectral analysis of compounds 3c - 3f are as follows:

[0153]

[0154] Compound 3c: Yield = 81.8%, white solid, mp 222 - 224 °C; 1 1H NMR (400 MHz, DMSO-d6) δ 6.43 (s, 1H, H-Ar), 4.09 (s, 2H, CH2), 2.49 (s, 3H, CH3), 1.96 (s, 3H, CH3), 1.34 (s, 3H, CH3). 13 13C NMR (100 MHz, DMSO-d6) δ 174.42, 162.28, 160.65, 140.64, 109.83, 107.12, 105.68, 63.86, 40.17, 24.44, 15.14, 8.37. MS (ESI) m / z: 211.10 [M+H] + .

[0155]

[0156] Compound 3d: Yield = 90.9%, yellow solid, mp 189 - 191 °C; 11H NMR (400 MHz, DMSO-d6) δ 6.43 (s, 1H, H-Ar), 3.98 (t, J = 6.4 Hz, 2H, CH2), 2.48 (s, 3H, CH3), 1.96 (s, 3H, CH3), 1.79–1.68 (m, 2H, CH2), 0.99 (t, J = 7.4 Hz, 3H, CH3). 13 13C NMR (100 MHz, DMSO-d6) δ 174.41, 162.27, 160.73, 140.66, 109.87, 107.16, 105.70, 69.59, 39.98, 24.42, 22.58, 10.86, 8.30. MS (ESI) m / z: 247.10 [M+Na] + .

[0157]

[0158] Compound 3e: Yield = 87.2%, yellow solid, mp 167 - 169 °C; 1 1H NMR (400 MHz, DMSO-d6) δ 6.46 (s, 1H, H-Ar), 4.70 (p, J = 6.0 Hz, 1H, CH), 2.49 (s, 3H, CH3), 1.94 (s, 3H, CH3), 1.28 (s, 3H, CH3), 1.27 (s, 3H, CH3). 13 13C NMR (100 MHz, DMSO-d6) δ 174.39, 162.56, 159.83, 140.43, 110.80, 108.38, 105.46, 70.15, 24.41, 22.51, 8.54. MS (ESI) m / z: 247.10 [M+Na] + .

[0159]

[0160] Compound 3f: Yield = 54.5%, yellow solid, mp 188 - 191 °C; 1 1H NMR (400 MHz, DMSO-d6) δ 6.45 (s, 1H, H-Ar), 6.05 (m, 1H, CH), 5.40 (m, 1H, CH=CH2), 5.26 (m, 1H, CH=CH2), 4.62 (dt, J = 5.0, 1.7 Hz, 2H, CHCH2), 2.48 (s, 3H, CH3), 1.98 (s, 3H, CH3). 1313C NMR (100 MHz, DMSO-d6) δ 174.38, 162.28, 160.19, 140.58, 133.98, 117.60, 110.04, 107.42, 105.96, 68.68, 24.44, 8.39. MS (ESI) m / z: 223.10 [M+H] + .

[0161] (2) Synthesis of phenolic intermediates:

[0162] Synthesis of compounds 5b - 5f: Weigh compound 4 (500 mg, 2.74 mmol) and KHCO3 (411.45 mg, 4.11 mmol) with an analytical balance and add them to a pre-prepared 50 mL round-bottom flask equipped with a stir bar. Then, measure 10 mL of DMF with a measuring cylinder and pipette the corresponding bromide (3.3 mmol) into it. After adding, fix the reaction system of the round-bottom flask on a thermostatic magnetic stirrer with an iron stand and iron clamp for reaction at room temperature. Every half hour, monitor the reaction by TLC until it is complete. Then add 20 mL of water, and slowly add 1 M hydrochloric acid to adjust the pH to 3 - 4 until a solid precipitates. Filter by suction and dry in an oven (35 °C) to obtain compounds 5b - 5f; the synthetic route is as follows:

[0163]

[0164] The physical properties and spectral analysis of compounds 5b - 5f are as follows:

[0165]

[0166] Compound 5b: Yield = 62%, yellow solid, mp 134 - 136 °C; 1 1H NMR (400 MHz, CDCl3) δ 12.12 (s, 1H, OH), 6.20 (s, 1H, H-Ar), 4.39 (q, 2H, CH2CH3), 2.47 (s, 3H, CH3), 2.10 (s, 3H, CH3), 1.41 (d, 3H, CH2CH3). 13 13C NMR (100 MHz, CDCl3) δ 172.34, 163.27, 158.10, 140.36, 110.70, 108.72, 105.46, 61.40, 24.32, 14.36, 7.79. MS (ESI) m / z: 211.10 [M+H] + .

[0167]

[0168] Compound 5c: Yield = 51.3%, yellow solid, mp 141 - 143 °C; 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H, OH), 10.12 (s, 1H, OH), 6.29 (s, 1H, H-Ar), 4.24 (t, J = 6.4 Hz, 2H, CH2), 2.40 (s, 3H, CH3), 1.94 (s, 3H, CH3), 1.73 (h, J = 7.0 Hz, 2H, CH2), 0.98 (t, J = 7.4 Hz, 3H, CH3). 13 C NMR (100 MHz, DMSO-d6) δ 172.16, 162.51, 160.51, 139.30, 111.04, 108.61, 104.29, 67.11, 40.40, 24.17, 21.91, 11.09, 8.44. MS (ESI) m / z: 247.10 [M+Na] + .

[0169]

[0170] Compound 5d: Yield = 49.1%, white solid, mp 89 - 92 °C; 1 H NMR (400 MHz, CDCl3) δ 12.18 (s, 1H, OH), 6.20 (s, 1H, H-Ar), 5.29 (p, J = 6.2 Hz, 1H, CH), 2.47 (s, 3H, CH3), 2.10 (s, 3H, CH3), δ 1.39 (d, J = 6.3 Hz, 6H, 2CH3). 13 C NMR (100 MHz, CDCl3) δ 171.68, 163.14, 157.85, 140.16, 110.50, 108.56, 105.65, 69.21, 24.30, 22.06, 7.66. MS (ESI) m / z: 247.10 [M+Na] + .

[0171]

[0172] Compound 5e: Yield = 79.4%, yellow solid, mp 219 - 222 °C; 11H NMR (400 MHz, CDCl3) δ 12.03 (s, 1H, OH-2), 6.20 (s, 1H, H-Ar), 6.16–5.89 (m, 1H, CHCH2), 5.46–5.26 (m, 2H, CHCH2), 4.84 (dt, J=5.8, 1.4 Hz, 2H, OCH2), 2.48 (s, 3H, CH3), 2.10 (s, 3H, CH3); 13 13C NMR (100 MHz, CDCl3) δ 172.00, 163.38, 158.23, 140.42, 131.96, 118.99, 110.76, 108.74, 105.29, 66.04, 24.43, 7.80. MS (ESI) m / z: 245.10 [M+Na] + .

[0173]

[0174] Compound 5f: Yield = 83.3%, yellow solid, mp 205 - 207 °C; 1 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H, OH), 10.25 (s, 1H, OH), 6.33 (s, 1H, H-Ar), 5.19 (s, 2H, CH2), 2.36 (s, 3H, CH3), 1.96 (s, 3H, CH3). 13 13C NMR (100 MHz, DMSO-d6) δ 169.39, 160.93, 160.51, 138.62, 116.02, 110.70, 108.55, 103.96, 49.49, 22.96, 8.07. MS (ESI) m / z: 244.10 [M+Na] + .

[0175] (3) Synthesis of derivatives:

[0176] Synthesis of compounds 6b - 6p': Weigh the corresponding benzoic acid intermediate (1.1 mmol) and the corresponding phenol (1.1 mmol) with an analytical balance and add them to a 50 mL round-bottom flask equipped with a magnetic stir bar. Measure 20 mL of dichloromethane with a graduated cylinder and add 0.31 mL of trifluoroacetic anhydride with a pipette. After the addition, fix the reaction system of the round-bottom flask on a thermostatic magnetic stirrer with an iron stand and iron clamp and react at room temperature. TLC was monitored every half hour until the reaction was complete. Then add 10 mL of water and extract twice with 30 mL of dichloromethane each time. Combine the organic layers, dry over anhydrous Na2SO4, filter, evaporate to dryness, and purify the crude product by column chromatography to obtain compounds 6b - 6p'; The synthetic route is as follows:

[0177]

[0178] The physical properties and spectral analysis of compound 6b-6p′ are as follows:

[0179]

[0180] Compound 6b: Yield = 45%, white solid, mp 177 - 180 °C; 1 H NMR(400MHz,CDCl3)δ11.93(s,1H,OH),11.51(s,1H,OH),6.52(s,1H,H-Ar),6.38(s,1H,H-Ar),3.98(s,3H,OCH3),3.90(s,3H,OCH3),2.69(s,3H,CH3),2.54(s,3H,CH3),2.10(s,3H,CH3),2.09(s,3H,CH3). 13 C NMR(100MHz,CDCl3)δ172.43,170.34,162.99,162.39,152.68,140.88,139.81,117.07,116.50,111.43,110.07,106.56,104.48,77.48,55.71,52.38,25.22,24.16,9.46,7.95.MS(ESI)m / z:375.1[M+H] + .HRMS(ESI)calcd for C 20 H 22 O7 Na[M+Na] + :397.1258,found397.1258.

[0181]

[0182] Compound 6e: Yield = 48%, white solid, mp 135 - 138 °C; 1 H NMR(400MHz,CDCl3)δ12.05(s,1H,OH),11.53(s,1H,OH),6.50(s,1H,H-Ar),6.38(s,1H,H-Ar),5.34(p,J=6.3Hz,1H,CH),3.90(s,3H,CH3),2.69(s,3H,CH3),2.55(s,3H,CH3),2.10(s,3H,CH3),2.08(s,3H,CH3),1.41(d,J=6.3Hz,6H,2CH3). 1313C NMR (100 MHz, CDCl3) δ 171.33, 170.27, 162.99, 162.84, 162.24, 152.32, 140.75, 116.93, 116.29, 111.30, 110.42, 106.42, 104.39, 69.87, 55.59, 25.10, 24.23, 21.99, 9.31, 7.82. MS (ESI) m / z: 403.1 [M+H] + . HRMS (ESI) calcd for C 21 H 26 O7Na [M+Na] + : 425.1571, found 425.1571.

[0183]

[0184] Compound 6n: Yield = 36.1%, white solid, mp 129 - 131 °C; 1 1H NMR (400 MHz, CDCl3) δ 11.93 (s, 1H, OH), 11.52 (s, 1H, OH), 7.47 - 7.33 (m, 5H, H - Ar), 6.51 (s, 1H, H - Ar), 6.36 (s, 1H, H - Ar), 5.43 (s, 2H, CH2), 4.12 (q, 2H, CH2), 2.67 (s, 3H, CH3), 2.53 (s, 3H, CH3), 2.11 (s, 3H, CH3), 2.10 (s, 3H, CH3), 1.46 (t, 3H, CH3). 13 13C NMR (100 MHz, CDCl3) δ 171.66, 170.26, 163.11, 163.03, 161.81, 152.66, 140.63, 139.81, 135.11, 128.75, 128.62, 128.51, 117.06, 116.48, 111.39, 109.89, 107.31, 104.10, 67.52, 63.86, 25.13, 24.40, 14.87, 9.37, 7.92. MS (ESI) m / z: 465.2 [M+H] + . HRMS (ESI) calcd for C 27 H 28 O7Na [M+Na] + : 487.1727, found 487.1727.

[0185]

[0186] Compound 6o: Yield = 33.1%, white solid, mp 110 - 113 °C; 1 H NMR (400 MHz, CDCl3) δ 11.91 (s, 1H, OH), 11.50 (s, 1H, OH), 6.51 (s, 1H, H-Ar), 6.34 (s, 1H, H-Ar), 4.00 (t, J = 6.4 Hz, 2H, CH2), 3.96 (s, 3H, CH3), 2.65 (s, 3H, CH3), 2.52 (s, 3H, CH3), 2.10 (s, 3H, CH3), 2.07 (s, 3H, CH3), 1.85 (p, J = 6.9, 6.5 Hz, 2H, CH2), 1.06 (t, J = 7.4 Hz, 3H, CH3). 13 C NMR (100 MHz, CDCl3) δ 172.32, 170.23, 163.08, 162.86, 161.92, 152.59, 140.62, 139.67, 116.96, 116.40, 111.45, 109.93, 107.35, 104.09, 69.74, 52.26, 25.07, 24.04, 22.64, 10.57, 9.33, 7.84. MS (ESI) m / z: 403.2 [M + H] + .HRMS (ESI) calcd for C 22 H 26 O7Na [M + Na] + : 425.1571, found 425.1571.

[0187]

[0188] Compound 6t: Yield = 36.7%, white solid, mp 112 - 115 °C; 1 H NMR (400 MHz, CDCl3) δ 12.05 (s, 1H, OH), 11.53 (s, 1H, OH), 6.50 (s, 1H, H-Ar), 6.36 (s, 1H, H-Ar), 5.34 (hept, 1H, CH), 4.01 (t, 2H, CH2), 2.67 (s, 3H, CH3), 2.54 (s, 3H, CH3), 2.11 (s, 3H, CH3), 2.08 (s, 3H, CH3), 1.85 (dtd, 2H, CH2), 1.42 (s, 3H, CH3), 1.41 (d, J = 6.3 Hz, 6H, 2CH3), 1.07 (t, 3H, CH3). 1313C NMR (100 MHz, CDCl3) δ 171.33, 170.35, 163.07, 162.84, 161.90, 152.36, 140.61, 139.65, 116.94, 116.32, 111.43, 110.40, 107.33, 104.12, 69.86, 69.73, 25.06, 24.23, 22.65, 21.99, 10.57, 9.31, 7.84. MS (ESI) m / z: 431.2 [M+H] + . HRMS (ESI) calcd for C 24 H 30 O7Na [M+Na] + : 453.1884, found 453.1884.

[0189]

[0190] Compound 6v: Yield = 29.3%, white solid, mp 111 - 114 °C; 1 1H NMR (400 MHz, CDCl3) δ 11.92 (s, 1H, OH), 11.51 (s, 1H, OH), 7.51–7.29 (m, 5H, H - Ar), 6.51 (s, 1H, H - Ar), 6.36 (s, 1H, H - Ar), 5.43 (s, 2H, CH2), 4.02 (t, J = 6.4 Hz, 2H, CH2), 2.67 (s, 3H, CH3), 2.52 (s, 3H, CH3), 2.11 (s, 3H, CH3), 2.09 (s, 3H, CH3), 1.86 (q, J = 6.5 Hz, 2H, CH2), 1.07 (t, J = 7.4 Hz, 3H, CH3). 13 13C NMR (100 MHz, CDCl3) δ 171.63, 170.22, 163.09, 163.01, 161.92, 152.66, 140.61, 139.77, 135.11, 128.74, 128.60, 128.49, 117.05, 116.46, 111.45, 109.90, 107.34, 104.11, 69.74, 67.49, 25.07, 24.35, 22.64, 10.58, 9.34, 7.84. MS (ESI) m / z: 479.2 [M+H] + . HRMS (ESI) calcd for C 28 H 30 O7Na [M+Na] + : 501.1884, found 501.1884.

[0191]

[0192] Compound 6u: Yield = 35.8%, white solid, mp 60 - 63 °C; 1 H NMR (400 MHz, CDCl3) δ 11.92 (s, 1H, OH), 11.53 (s, 1H, OH), 6.51 (s, 1H, H - Ar), 6.37 (s, 1H, H - Ar), 4.67 (p, J = 6.1 Hz, 1H, CH), 3.97 (s, 3H, CH3), 2.66 (s, 3H, CH3), 2.53 (s, 3H, CH3), 2.09 (s, 6H, 2CH3), 1.38 (d, J = 6.0 Hz, 6H, 2CH3). 13 C NMR (100 MHz, CDCl3) δ 172.32, 170.20, 163.42, 162.86, 161.04, 152.60, 140.32, 139.66, 116.97, 116.40, 112.38, 109.92, 108.60, 103.85, 70.37, 52.25, 25.10, 24.04, 22.29, 9.34, 8.07. MS(ESI) m / z: 403.2 [M + H] + .HRMS(ESI) calcd for C 22 H 26 O7Na [M + Na] + : 425.1571, found 425.1571.

[0193]

[0194] Compound 6a': Yield = 35.5%, white solid, mp 155 - 158 °C; 1 H NMR (400 MHz, CDCl3) δ 11.46 (s, 1H, OH), 11.28 (s, 1H, OH), 6.57 (s, 1H, H - Ar), 6.37 (s, 1H, H - Ar), 5.01 (s, 2H, CH2), 4.67 (p, J = 6.0 Hz, 1H, CH), 2.66 (s, 3H, CH3), 2.57 (s, 3H, CH3), 2.10 (s, 3H, CH3), 2.09 (s, 3H, CH3), 1.38 (d, J = 6.0 Hz, 6H, 2CH3). 1313C NMR (100 MHz, CDCl3) δ 170.22, 170.02, 163.49, 161.17, 153.72, 140.33, 139.85, 117.61, 117.20, 113.88, 112.42, 108.65, 108.19, 103.67, 70.40, 48.93, 25.11, 24.21, 22.28, 9.36, 8.06. MS (ESI) m / z: 428.2 [M+H] + . HRMS (ESI) calcd for C 23 H 25 NO7Na [M+Na] + : 450.1523, found 450.1523.

[0195]

[0196] Compound 6b′: Yield = 40.4%, white solid, mp 83 - 86 °C; 1 1H NMR (400 MHz, CDCl3) δ 11.91 (s, 1H, OH), 11.53 (s, 1H, OH), 7.47–7.33 (m, 5H, H-Ar), 6.50 (s, 1H, H-Ar), 6.36 (s, 1H, H-Ar), 5.42 (s, 2H, CH2), 4.66 (p, J = 6.1 Hz, 1H, CH), 2.65 (s, 3H, CH3), 2.51 (s, 3H, CH3), 2.08 (s, 6H, 2CH3), 1.37 (d, J = 6.0 Hz, 6H 2CH3). 13 13C NMR (100 MHz, CDCl3) δ 171.64, 170.21, 163.43, 163.01, 161.05, 152.68, 140.32, 139.78, 135.12, 128.74, 128.60, 128.49, 117.06, 116.48, 112.38, 109.89, 108.61, 103.85, 70.37, 67.50, 25.11, 24.36, 22.29, 9.35, 8.08. MS (ESI) m / z: 479.2 [M+H] + . HRMS (ESI) calcd for C 28 H 30 O7Na [M+Na] + : 501.1884, found 501.1884.

[0197]

[0198] Compound 6j': Yield = 34.7%, white solid, mp 131 - 134 °C; 1 H NMR (400 MHz, CDCl3) δ 11.93 (s, 1H, OH), 11.54 (s, 1H, OH), 7.48 - 7.33 (m, 5H, H - Ar), 6.52 (s, 1H, H - Ar), 6.45 (s, 1H, H - Ar), 5.18 (s, 2H, OCH2), 3.98 (s, 3H, OCH3), 2.67 (s, 3H, CH3), 2.54 (s, 3H, CH3), 2.18 (s, 3H, CH3), 2.09 (s, 3H, CH3). 13 C NMR (100 MHz, CDCl3) δ 172.75, 170.63, 163.61, 163.31, 161.87, 152.99, 141.12, 140.14, 137.10, 129.10, 128.49, 127.53, 117.38, 116.80, 112.28, 110.41, 108.13, 105.01, 70.42, 52.71, 25.55, 24.49, 9.79, 8.54. MS (ESI) m / z: 451.2 [M + H] + . HRMS (ESI) calcd for C 26 H 26 O7Na [M + Na] + : 473.1571, found 473.1571.

[0199]

[0200] Compound 6k': Yield = 39.5%, white solid, mp 123 - 126 °C; 1 H NMR (400 MHz, CDCl3) δ 12.00 (s, 1H, OH), 11.54 (s, 1H, OH), 7.47–7.32 (m, 5H, H - Ar), 6.51 (s, 1H, H - Ar), 6.44 (s, 1H, H - Ar), 5.17 (s, 2H, CH2), 4.45 (q, J = 7.1 Hz, 2H, CH2), 2.67 (s, 3H, CH3), 2.55 (s, 3H, CH3), 2.17 (s, 3H, CH3), 2.08 (s, 3H, CH3), 1.43 (t, J = 7.1 Hz, 3H, CH3). 1313C NMR (100 MHz, CDCl3) δ 171.84, 170.22, 163.17, 162.89, 161.42, 152.42, 140.68, 139.74, 136.66, 128.66, 128.05, 127.09, 116.94, 116.32, 111.84, 110.12, 107.69, 104.59, 69.98, 61.76, 25.10, 24.14, 14.21, 9.34, 8.11. MS (ESI) m / z: 465.2 [M+H] + . HRMS (ESI) calcd for C 27 H 28 O7Na [M+Na] + : 487.1727, found 487.1727.

[0201] (5) Synthesis of ether compounds:

[0202] Prepare a clean 100 mL round-bottom flask equipped with a magnetic stir bar in advance. Weigh 1.2 mmol of KOH and measure 11 mL of DMSO:water = 10:1 using a graduated cylinder and add them thereto. After the KOH is completely dissolved, add 1 mmol of the corresponding acylhydrazone; fix the reaction system on a thermostatic magnetic stirrer with an iron stand and iron clamp and react at room temperature. After detecting by TLC (petroleum ether:ethyl acetate = 3:1) every 30 min until the reaction is complete, slowly add 1 M hydrochloric acid to adjust the pH to 1-2. Solid powder precipitates, filter by suction, and dry in an oven (35 °C) to obtain 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k;

[0203] The rearrangement reaction synthesis route diagram of the obtained target compounds 9a-9k is as follows:

[0204]

[0205] The physical properties and spectral analysis of compounds 9a-9k are as follows:

[0206]

[0207] Compound 9a: Yield = 51.8%, white solid, mp 216-220 °C; 1 1H NMR (400 MHz, Methanol-d4) δ 6.78 (s, 1H, H-Ar), 5.78 (s, 1H, H-Ar), 3.90 (s, 3H, CH3), 3.88 (s, 3H, CH3), 2.39 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.19 (s, 3H, CH3), 1.88 (s, 3H, CH3).13 13C NMR (100 MHz, Methanol-d4) δ 172.33, 169.46, 162.17, 159.87, 159.38, 150.00, 139.64, 135.51, 121.10, 117.05, 110.62, 109.00, 108.18, 105.96, 54.92, 50.91, 22.99, 18.73, 7.67, 6.87. MS (ESI) m / z: 375.1 [M+H] + . (ESI) calcd for C 20 H 22 O7Na [M+Na] + : 397.1258, found 397.1258.

[0208]

[0209] Compound 9b: Yield = 72.5%, light brown liquid, 1 1H NMR (400 MHz, CDCl3) δ 11.90 (s, 1H, OH), 7.43–7.30 (m, 5H, H-Ar), 6.60 (s, 1H, H-Ar), 5.78 (s, 1H, H-Ar), 5.36 (s, 2H, CH2), 3.87 (s, 3H, OCH3), 2.44 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.22 (s, 3H, CH3), 1.88 (s, 3H, CH3). 13 13C NMR (100 MHz, CDCl3) δ 171.88, 169.98, 162.81, 160.08, 159.63, 150.86, 139.99, 136.95, 135.47, 128.63, 128.40, 128.39, 119.61, 117.77, 111.23, 109.43, 108.49, 106.04, 66.97, 55.72, 24.70, 20.65, 8.95, 8.12. MS (ESI) m / z: 451.2 [M+H] + . HRMS (ESI) calcd for C 26 H 26 O7Na [M+Na] + : 473.1570, found 473.1570.

[0210]

[0211] Compound 9c: Yield = 69.5%, white solid, mp 183 - 186 °C;1 1H NMR (400 MHz, CDCl3) δ 11.99 (s, 1H, OH), 7.50–7.31 (m, 5H, H-Ar), 6.71 (s, 1H, H-Ar), 5.78 (s, 1H, H-Ar), 5.14 (s, 2H, CH2), 4.38 (q, J = 7.1 Hz, 2H, CH2), 2.44 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.22 (s, 3H, CH3), 1.95 (s, 3H, CH3), 1.38 (t, J = 7.1 Hz, 3H, CH3). 13 13C NMR (100 MHz, CDCl3) δ 172.12, 170.43, 162.76, 159.76, 159.07, 151.28, 139.93, 137.40, 136.56, 128.65, 128.10, 127.22, 119.20, 118.48, 111.26, 110.94, 108.30, 106.40, 70.32, 61.23, 24.53, 20.81, 14.25, 9.21, 8.10. MS (ESI) m / z: 465.2 [M+H] + . HRMS (ESI) calcd for C 27 H 28 O7Na [M+Na] + : 487.1727, found 487.1727.

[0212]

[0213] Compound 9d: Yield = 87.4%, white solid, mp 190 - 193 °C; 1 1H NMR (400 MHz, CDCl3) δ 11.90 (s, 1H, OH), 7.45–7.27 (m, 5H, H-Ar), 6.59 (s, 1H, H-Ar), 5.75 (s, 1H, H-Ar), 5.36 (s, 2H, CH2), 4.08 (q, J = 6.9 Hz, 2H, CH2), 2.43 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.21 (s, 3H, CH3), 1.88 (s, 3H, CH3), 1.45 (t, J = 6.9 Hz, 3H, CH3). 1313C NMR (100 MHz, CDCl3) δ 171.88, 170.78, 162.90, 159.96, 159.54, 151.32, 139.98, 137.66, 135.50, 128.63, 128.40, 128.37, 118.27, 118.10, 111.33, 110.50, 108.34, 106.16, 66.99, 64.08, 24.72, 20.92, 14.79, 9.01, 8.09. MS (ESI) m / z: 465.2 [M+H] + . HRMS (ESI) calcd for C 27 H 28 O7Na [M+Na] + : 487.1727, found 487.1727.

[0214]

[0215] Compound 9e: Yield = 74.3%, white solid, mp 222 - 226 °C; 1 1H NMR (400 MHz, CDCl3) δ 11.91 (s, 1H, OH), 7.48–7.31 (m, 5H, H-Ar), 6.70 (s, 1H, H-Ar), 5.80 (s, 1H, H-Ar), 5.13 (s, 2H, CH2), 3.90 (s, 3H, CH3), 2.44 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.23 (s, 3H, CH3), 1.95 (s, 3H, CH3). 13 13C NMR (100 MHz, CDCl3) δ 172.58, 169.91, 162.68, 159.95, 158.87, 151.04, 139.91, 137.03, 136.60, 128.64, 128.08, 127.22, 119.76, 118.36, 111.19, 110.88, 108.41, 106.20, 70.31, 51.84, 24.45, 20.68, 9.20, 8.13. MS (ESI) m / z: 451.2 [M+H] + . HRMS (ESI) calcd for C 26 H 26 O7Na [M+Na] + : 473.1571, found 473.1571.

[0216]

[0217] Compound 9f: Yield = 81%, white solid, mp 206 - 210 °C; 1 H NMR (400 MHz, CDCl3) δ 12.04 (s, 1H, OH), 6.61 (s, 1H, H-Ar), 5.78 (s, 1H, H-Ar), 5.27 (p, J = 6.3 Hz, 1H, CH), 3.88 (s, 3H, CH3), 2.45 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.23 (s, 3H, CH3), 1.89 (s, 3H, CH3), 1.37 (s, 3H, CH3), 1.36 (s, 3H, CH3). 13 C NMR (100 MHz, CDCl3) δ 171.63, 162.67, 159.77, 150.93, 139.86, 137.06, 117.81, 111.17, 109.43, 108.37, 106.57, 69.18, 55.74, 24.61, 22.04, 20.69, 8.97, 8.12. MS (ESI) m / z: 403.2 [M+H] + . HRMS (ESI) calcd for C 22 H 26 O7Na [M+Na] + : 425.1571, found 425.1571.

[0218]

[0219] Compound 9g: Yield = 76.9%, white solid, mp 234 - 237 °C; 1 H NMR (400 MHz, CDCl3) δ 11.90 (s, 1H, OH), 6.60 (s, 1H, H-Ar), 5.80 (s, 1H, H-Ar), 3.98 (t, J = 6.4 Hz, 2H, CH2), 3.90 (s, 3H, CH3), 2.44 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.23 (s, 3H, CH3), 1.90 (s, 3H, CH3), 1.84 (p, J = 7.1 Hz, 2H, CH2), 1.06 (t, J = 7.4 Hz, 3H, CH3). 1313C NMR (100 MHz, CDCl3) δ 172.59, 170.03, 162.66, 159.97, 159.39, 151.05, 139.88, 137.20, 118.93, 118.01, 111.18, 110.43, 108.41, 106.16, 69.96, 51.84, 24.44, 22.61, 20.77, 10.60, 8.94, 8.12. MS(ESI) m / z: 403.2 [M+H] + . HRMS(ESI) calcd for C 22 H 26 O7Na [M+Na] + : 425.1571, found 425.1571.

[0220]

[0221] Compound 9h: Yield = 92%, white solid, mp 232 - 236 °C; 1 1H NMR (400 MHz, CDCl3) δ 11.90 (s, 1H, OH), 6.63 (s, 1H, H - Ar), 5.78 (s, 1H, H - Ar), 4.62 (hept, J = 6.0 Hz, 1H, CH), 3.90 (s, 3H, OCH3), 2.43 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.21 (s, 3H, CH3), 1.87 (s, 3H, CH3), 1.37 (s, 6H, 2CH3). 13 13C NMR (100 MHz, CDCl3) δ 172.57, 171.14, 162.72, 159.88, 158.68, 151.55, 139.84, 137.39, 119.15, 118.21, 112.16, 111.23, 108.30, 106.21, 70.83, 51.80, 24.44, 22.14, 20.90, 9.20, 8.06. MS(ESI) m / z: 403.2 [M+H] + . HRMS(ESI) calcd for C 22 H 26 O7Na [M+Na] + : 425.1571, found 425.1571.

[0222]

[0223] Compound 9i: Yield = 94.7%, white solid, mp 226 - 230 °C; 11H NMR (400 MHz, CDCl3) δ 12.05 (s, 1H, OH), 6.60 (s, 1H, H-Ar), 5.76 (s, 1H, H-Ar), 5.33–5.22 (m, 1H, CH), 3.99 (t, J = 6.6 Hz, 2H, CH2), 2.45 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.21 (s, 3H, CH3), 1.89 (s, 3H, CH3), 1.84 (dt, J = 13.9, 7.0 Hz, 2H, CH2), 1.37 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.06 (t, J = 7.4 Hz, 3H, CH3). 13 13C NMR (100 MHz, CDCl3) δ 171.61, 170.97, 162.74, 159.67, 159.65, 151.38, 139.82, 137.66, 118.25, 118.17, 111.27, 110.49, 108.24, 106.66, 69.96, 69.15, 24.62, 22.60, 22.04, 20.92, 10.59, 8.96, 8.06. MS (ESI) m / z: 431.2 [M+H] + . HRMS (ESI) calcd for C 24 H 30 O7Na [M+Na] + : 453.1884, found 453.1884.

[0224]

[0225] Compound 9j: Yield = 87.9%, white solid, mp 52 - 56 °C; 1 1H NMR (400 MHz, CDCl3) δ 11.90 (s, 1H, OH), 7.44–7.29 (m, 5H, H-Ar), 6.62 (s, 1H, H-Ar), 5.76 (s, 1H, H-Ar), 5.36 (s, 2H, CH2), 4.61 (hept, J = 6.1 Hz, 1H, CH), 2.43 (s, 3H, CH3), 2.32 (s, 3H, CH3), 2.21 (s, 3H, CH3), 1.86 (s, 3H, CH3), 1.40–1.33 (m, 6H, 2CH3). 1313C NMR (100 MHz, CDCl3) δ 171.88, 170.67, 162.89, 159.94, 158.67, 151.52, 139.99, 137.41, 128.63, 128.41, 128.37, 119.14, 118.19, 112.20, 111.32, 108.38, 106.16, 70.85, 66.99, 24.72, 20.91, 9.20, 8.09. MS (ESI) m / z: 479.2 [M+H] + . HRMS (ESI) calcd for C 28 H 30 O7Na [M+Na] + : 501.1884, found 501.1884.

[0226]

[0227] Compound 9k: Yield = 61.4%, white solid, mp 175 - 178 °C; 1 1H NMR (400 MHz, CDCl3) δ 11.90 (s, 1H, OH), 7.43–7.29 (m, 5H, H-Ar), 6.60 (s, 1H, H-Ar), 5.76 (s, 1H, H-Ar), 5.36 (s, 2H, CH2), 3.98 (t, J = 6.5 Hz, 2H, CH2), 2.43 (s, 3H, CH3), 2.32 (s, 3H), 2.22 (s, 3H, CH3), 1.89 (s, 3H, CH3), 1.84 (dt, J = 13.9, 7.0 Hz, 2H, CH2), 1.06 (t, J = 7.4 Hz, 3H, CH3). 13 13C NMR (100 MHz, CDCl3) δ 171.88, 162.89, 159.98, 159.95, 159.62, 151.27, 139.99, 137.68, 135.49, 128.63, 128.41, 128.38, 118.12, 111.32, 110.51, 108.37, 106.17, 106.16, 69.97, 66.98, 24.72, 22.60, 20.90, 10.59, 8.95, 8.10. MS (ESI) m / z: 479.2 [M+H] + . HRMS (ESI) calcd for C 28 H 30 O7Na [M+Na] +: 501.1884, found 501.1884. Among them, the conformation of 9a was determined by X-ray single crystal diffraction, see Figure 34 .

[0228] Example 2

[0229] Take any one or more of the compounds 9a - 9k as raw materials, add the pharmaceutically acceptable excipient dextrin, granulate to obtain granules.

[0230] Example 3

[0231] Take any one or more of the compounds 9a - 9k as raw materials, add the pharmaceutically acceptable excipient dextrin, mix well, fill into capsules to obtain capsules.

[0232] Example 4

[0233] Take any one or more of the compounds 9a - 9k as raw materials, add the pharmaceutically acceptable excipient dextrin, granulate, and tabletten to obtain tablets.

[0234] Example 5

[0235] Take any one or more of the compounds 9a - 9k as raw materials, add the pharmaceutically acceptable excipient dextrin, mix well, pill, and dry to obtain pills.

[0236] Example 6

[0237] Take any one or more of the compounds 9a - 9k as raw materials, add 10 times the amount of injection water, mix well, filter, sterilize to obtain injections.

[0238] In order to further verify the feasibility and effectiveness of the present invention, the inventors conducted a series of experiments as follows:

[0239] 1. Instruments and Materials

[0240] 1.1 Experimental Instruments

[0241] The experimental instruments and reagents are shown in Table 1 below.

[0242] Table 1 Experimental Instruments and Reagents

[0243]

[0244]

[0245] 1.2 Experimental Materials and Experimental Conditions

[0246] Cells: Canine renal distal tubule MDCK cells purchased from Shanghai Aolu Biotechnology Co., Ltd.;

[0247] Culture medium: 10% fetal bovine serum + 1% double antibody + 89% high-glucose medium;

[0248] Drugs: 100 μmol / mL derivatives (9a - 9k), hydrochlorothiazide, 15 mg / mL NaCl, and 30 mmol / L CaC2O4 (all prepared with DMEM).

[0249] Incubator conditions: Temperature 37°C, relative humidity 95%, 5% CO2.

[0250] Proliferation rate (%) = (Absorbance (OD) of sample group - OD value of blank group) / OD value of blank group × 100%

[0251] Inhibition rate (%) = (OD value of blank group - Absorbance (OD) of sample group) / OD value of blank group × 100%

[0252] Note: Due to Na + , Cl - or Ca 2+ Based on the detection principle of the kit, the higher the concentration in the liquid, the darker the color after adding the reaction solution in the kit, and the larger the OD value; for the CaC2O4 2- Detection principle of the method: The higher the concentration in the liquid, the slower the potassium permanganate fades (from purple to colorless), so the smaller the OD value.

[0253] 2. Experimental methods

[0254] 2.1 MTT method for detecting cytotoxicity

[0255] (1) Take DMCK cells in the logarithmic growth phase and inoculate them in a 96-well plate (10 4 cells / well), place them in the incubator for 24 h, then discard the culture medium solution and add drugs. Set up a normal group (DMEM liquid), a drug administration group (9a - 9k), and a hydrochlorothiazide control group. Add 100 μL of drug to each well, and then continue to culture for 24 h. Then discard the drug solution, replace it with DMEM solution, add 20 μL of MTT (5 mg / mL) to each well, continue to culture for 4 h, then aspirate and discard the mixed liquid in the wells, add 150 μL of DMSO to each well, shake and mix well for 10 min, and then detect the absorbance (OD) of each well at 490 nm.

[0256] (2) Results of cytotoxicity study

[0257] The results of the MTT method for detecting the cytotoxic effects of each drug on MDCK cells showed (Table 2, Figure 35 ), at a concentration of 100 μmol / mL, the ether compounds (9a - 9k) were all toxic to MDCK cells. Except for 9a (-3.02) and 9b (-2.53), the other ether compounds had significant toxicity (P < 0.05).

[0258] Table 2 MTT method for detecting cell proliferation ability

[0259]

[0260]

[0261] Note: For the average proliferation rate, a positive value indicates a promoting effect, and a negative value indicates an inhibitory effect. * Indicates: P < 0.05.

[0262] 2.2 The MTT method was used to determine the growth inhibitory activities of target compounds 9a - 9k against three cancer cells (A549, HePG2, and 22RV1).

[0263] (1) Logarithmically growing cells were seeded in 96 - well culture plates (about 10,000 cells per well). The cells were cultured in a medium containing 10% fetal bovine serum, 1% penicillin - streptomycin, and 89% basal medium, and incubated in a 37°C constant - temperature cell culture incubator with 5% CO2 and 95% humidity for 24 hours. A positive control group (sorafenib and 5 - fluorouracil), a blank group (containing cells, medium, MTT, and DMSO), and a dosing group were set up. The dosing group was complete medium containing different compound concentrations of 100 μmol / L, and 100 μL was added to each well. After incubation for 72 hours, each group had 3 replicate wells. After the incubation ended, the liquid medicine in each well was aspirated, 100 μL of basal medium was added, and then 20 μL of MTT solution (added in the dark) was added to each well. The plate was put back into the incubator for 4 hours. The supernatant was gently aspirated, 150 μL of DMSO was added to each well, and after shaking and mixing for 10 minutes, the absorbance (OD) value at 490 nm was measured using a microplate reader. The inhibition rate was calculated according to the formula: Inhibition Rate = (Average OD value of the blank group - Average OD value of the dosing group) / Average OD value of the blank group × 100%. Subsequently, the inhibition rates (%) of 9a - 9k at 7 concentrations against A549 cells, HepG2 cells, and 22RV1 cells were obtained, and the IC 50 value was calculated according to the Logit method.

[0264] (2) Experimental results:

[0265] Table 1: Inhibitory activity effects of the compounds involved in the present invention against three tumor cells

[0266]

[0267] Conclusion: The results showed that compounds 9a, 9c, 9e and 9f prepared by the present invention had moderate cytotoxic activities against A549 cells, and the half-inhibitory concentration values were 2.61, 1.43 and 2.21 mmol / L, respectively. Compounds 9a-d, i-j had high cytotoxic activities against HepG2 cells, with good activities, and the half-inhibitory concentration values were 0.41 - 1.56 mmol / L. Compound 9d had the best anti-proliferative activity against 22RV1 cells, and the half-inhibitory concentration value was 0.78 mmol / L. The results indicated that the derivatives synthesized in this study had potential anti-tumor activities.

[0268] Although the present invention has been described in detail above with general descriptions, specific embodiments and experiments, some modifications or improvements can be made based on the present invention, which are obvious to those skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection required by the present invention.

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Claims

1. A barbatic acid ether derivative, characterized in that, Its chemical general formula is: ； Its specific structure is as follows: Compound 9a Compound 9b Compound 9c Compound 9d Compound 9e Compound 9f Compound 9g Compound 9h Compound 9i Compound 9j Compound 9k.

2. A method for synthesizing the barbatic acid ether derivative as described in claim 1, characterized in that, Using bamabate esters as raw materials, an intramolecular rearrangement reaction is mediated by potassium hydroxide. The specific steps are as follows: In a clean 100 mL round-bottom flask equipped with a magnetic stir bar, weigh 1.2 mmol of KOH and measure 11 mL of DMSO aqueous solution with a measuring cylinder and add it thereto. After the KOH is completely dissolved, add 1 mmol of the corresponding bamabate ester derivative; fix the reaction system on a thermostatic magnetic stirrer with an iron stand and iron clamp and react at room temperature. After TLC detection every 30 min until the reaction is complete, slowly add 1 M hydrochloric acid to adjust the pH to 1-2. Solid powder precipitates, filter by suction, and dry in an oven to obtain pure products of the target compounds 9a-9k.

3. The synthesis method of the barbanic acid ether derivative according to claim 2, characterized in that, The bamabate ester derivatives are obtained by using oak moss as a raw material, through substitution, hydrolysis to synthesize the corresponding benzoic acid intermediates and phenolic intermediates, and then through an esterification reaction.

4. The synthesis method of the baba ether derivatives according to claim 2, characterized in that, The volume ratio of the DMSO aqueous solution is: DMSO: water = 10:

1.

5. The synthesis method of the barbatic acid ether derivative according to claim 2, characterized in that, The reagent for TLC detection is: petroleum ether: ethyl acetate = 3:

1.

6. The synthesis method of the barbatic acid ether derivative according to claim 2, characterized in that, The drying temperature in the oven is 35 °C.

7. Use of the ether compounds 9a-9k obtained by the synthesis method of the bamabate ether derivatives as described in claim 2 in the preparation of anti-tumor drugs or preparations.

8. Use of the barbituric acid ether derivative according to claim 7, characterized in that, The preparation is prepared into a pharmaceutically acceptable preparation by adding pharmaceutically acceptable excipients, and the pharmaceutically acceptable preparation is a solid preparation or a liquid preparation.

9. Use of the barbanic acid ether derivative according to claim 8, characterized in that, The solid preparation is a granule, a capsule, a tablet, a pill; the liquid preparation is an injection preparation, an oral liquid.

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