Azaphilone compound as well as derivative, preparation method and application thereof

Abstract

The invention belongs to the technical field of novel Azaphilone synthesis, and particularly relates to an Azaphilone compound, a derivative of the Azaphilone compound, a preparation method of the Azaphilone compound and application of the Azaphilone compound and the derivative of the Azaphilone compound. The preparation method provided by the invention has the characteristics of simple and easily available initial raw materials, good functional group compatibility, compatibility of electron donating groups, electron withdrawing groups, heterocyclic rings, condensed rings, aryl groups and fatty groups, high reaction selectivity, high yield, few byproducts, cheap and commercially available catalyst, simple post-treatment, environmental friendliness and the like. The Azaphilone compound and the derivative thereof prepared by the invention have the effect of activating the antitumor activity of NK cells, can be used for preparing antitumor drugs, and have important application value.

Description

Technical Field

[0001] The present invention belongs to the technical field of novel Azaphilone synthesis, and particularly relates to an Azaphilone compound, its derivatives, and a preparation method and application thereof. Background Art

[0002] The information disclosed in the background art of the present invention is only intended to increase the understanding of the overall background of the present invention, and is not necessarily regarded as an admission or an indication in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Natural products have been proven to be an important source of drug entities, and approximately 49% of anti-tumor small molecule drugs directly or indirectly originate from natural products. Polyketides are one of the most structurally diverse natural products, including compounds containing simple aromatic hydrocarbons to highly modified complex aromatic hydrocarbons, and fungi have always been considered the main source of bioactive polyketides. Azaphilone compounds are a family of fungal polyketide metabolites with variable structures, having a highly oxidized pyranodione bicyclic core, commonly known as isochromene, and a quaternary carbon chiral center. They exhibit excellent activities in various bioactivity tests, such as inhibiting gp120-CD4 binding, inhibiting Grb2-SH2 interaction, and inhibiting dihydrofolate reductase, and their prospects for drug physiological activities have attracted extensive attention and research. In 2019, Ocean University of China isolated a series of novel-structured Azaphilones from the metabolites of deep-sea sediment fungi. These compounds exhibit broad-spectrum cytotoxicity, are active against MGC-803 and HO8910, with IC50 values of 6.6 and 9.7 μM respectively (Reference: Sun, C., Ge, X., Li, D. Mar. Drugs, 2019, 17, 253.), and there has been no reported total synthesis research on this new-structured Azaphilone. Therefore, exploring the synthesis process and structurally modifying and synthesizing around this molecule to support drug research has become crucial. Summary of the Invention

[0004] Aiming at the deficiencies of the prior art, the first object of the present invention is to provide an Azaphilone compound.

[0005] The second object of the present invention is to provide a preparation method for the above-mentioned Azaphilone compound.

[0006] The third object of the present invention is to provide derivatives of the above-mentioned Azaphilone compound.

[0007] The fourth object of the present invention is to provide a preparation method for the above-mentioned derivatives.

[0008] The fifth object of the present invention is to provide the applications of the above-mentioned Azaphilone compounds and their derivatives.

[0009] To achieve the above object, the present invention provides the following technical solutions:

[0010] An Azaphilone compound, the general structural formula of the Azaphilone compound is shown in formula (I);

[0011]

[0012] In formula (I), the R 1 is hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) or iodine (I); the R 2 is methyl, ethyl, cis-2-butene, phenyl, furyl or thiophenyl.

[0013] Furthermore, the structural formula of the Azaphilone compound is any one of the following:

[0014]

[0015] The preparation method of the above-mentioned Azaphilone compound, the preparation method adopts the following steps: under an oxygen-free condition, add the compound shown in formula (III) to the organic solvent solution of the compound shown in formula (II), stir, add a catalyst, heat and react to obtain the Azaphilone compound shown in formula (I); the reaction route is shown in Route 1:

[0016]

[0017] Furthermore, the molar volume ratio of the compound shown in formula (II), the compound shown in formula (III), the catalyst and the organic solvent is 1.00 mol: 1.50 mol: 2.00 mol: 3.00 L.

[0018] Furthermore, the stirring adopts the following steps: first stir at room temperature for 10 min, and then stir at 110 °C for 1 h.

[0019] Furthermore, the heating reaction is carried out under stirring, the temperature is 110 °C, and the time is 1 h.

[0020] Furthermore, the organic solvent is toluene, tetrahydrofuran, carbon tetrachloride or dichloroethane.

[0021] Furthermore, the catalyst is triethylamine or diisopropylethylamine.

[0022] Furthermore, after the reaction is completed, the reaction solution needs to be quenched with 1M HCl. The obtained solution is extracted three times with ethyl acetate, dried with anhydrous sodium sulfate, and then concentrated under vacuum and reduced pressure. Using petroleum ether and ethyl acetate as eluents, silica gel column chromatography purification is carried out to obtain the Azaphilone compound.

[0023] Furthermore, the oxygen isolation condition is an inert atmosphere condition. Conducting the synthesis under these protective atmospheres helps the reaction proceed in the forward direction.

[0024] Derivatives of the above-mentioned Azaphilone compounds, the general structural formula of the derivatives is shown in Formula (IV);

[0025]

[0026] In Formula (IV), the R 3 is benzyl, naphthyl or an aliphatic chain group.

[0027] Furthermore, the structural formula of the derivative is any one of the following:

[0028]

[0029] The preparation method of the above-mentioned derivative adopts the following steps: Add acetic acid (CH3COOH) and the compound shown in Formula (V) to the organic solvent solution of the compound shown in Formula (I), stir, and react to obtain the derivative shown in Formula (IV); the reaction route is shown in Route 2:

[0030]

[0031] Furthermore, the molar volume ratio of the compound shown in Formula (I), the compound shown in Formula (V), acetic acid and the organic solvent is 1.00 mol: 1.20 mol: 3.60 mol: 3.00 L.

[0032] Furthermore, the organic solvent is toluene, tetrahydrofuran, carbon tetrachloride or dichloroethane.

[0033] Furthermore, the stirring time is 10 min.

[0034] Furthermore, the reaction is carried out at room temperature.

[0035] Furthermore, after the reaction is completed, the reaction solution needs to be concentrated under vacuum and reduced pressure, and silica gel column chromatography purification is carried out using petroleum ether and ethyl acetate as eluents to obtain the derivative.

[0036] Furthermore, the preparation method of the compound shown in Formula (II) adopts the following steps:

[0037] (1) Add cuprous iodide and bis(triphenylphosphine)palladium dichloride to the dimethylformamide (DMF) solution of the compound shown in formula (VI), then add compound A (dec-1-yne) and triethylamine, and carry out a heating reaction to obtain the compound shown in formula (VII); the reaction route is as shown in Route 3:

[0038]

[0039] (2) Add silver nitrate and trifluoroacetic acid to the dichloromethane (DCM) solution of the compound shown in formula (VII), stir at room temperature for 30 min, add 2-iodoxybenzoic acid and tetrabutylammonium bromide, and carry out a reaction at room temperature to obtain the compound shown in formula (VIII);

[0040]

[0041] (3) Add N-chlorosuccinimide to the acetonitrile (CH3CN) solution of the compound shown in formula (VIII) obtained in step (2), and carry out a reaction at room temperature for 24 h to obtain the compound shown in formula (IX); the molar volume ratio of the compound shown in formula (VIII), N-chlorosuccinimide and acetonitrile is 1.00 mol: 1.20 mol: 2.00 L;

[0042]

[0043] Alternatively, add N-bromosuccinimide to the acetonitrile solution of the compound shown in formula (VIII) obtained in step (2), and carry out a reaction at room temperature for 6 h to obtain the compound shown in formula (X); the molar volume ratio of the compound shown in formula (VIII), N-bromosuccinimide and acetonitrile is 1.00 mol: 1.20 mol: 2.00 L;

[0044]

[0045] Alternatively, add N-iodosuccinimide to the acetonitrile solution of the compound shown in formula (VIII) obtained in step (2), and carry out a reaction at room temperature for 3 h to obtain the compound shown in formula (XI); the molar volume ratio of the compound shown in formula (VIII), N-iodosuccinimide and acetonitrile is 1.00 mol: 1.20 mol: 2.00 L;

[0046]

[0047] The compound shown in formula (II) includes the compound shown in formula (VIII), the compound shown in formula (IX), the compound shown in formula (X) and the compound shown in formula (XI).

[0048] Further, in step (1), the molar volume ratio of the compound shown in formula (VI), cuprous iodide, bis(triphenylphosphine)palladium dichloride, decyne, triethylamine, and dimethylformamide is 1.00 mol: 0.10 mol: 0.10 mol: 1.50 mol: 3.28 mol: 5.00 L; the temperature of the heating reaction is 60 °C and the time is 16 h;

[0049] After the reaction is completed, it is also necessary to quench with 1 M hydrochloric acid, filter with diatomaceous earth, extract the obtained solution three times with ethyl acetate, dry with anhydrous sodium sulfate, perform vacuum concentration and reduced pressure concentration, and use petroleum ether and ethyl acetate as eluents to obtain the compound shown in formula (VII) through silica gel column chromatography purification.

[0050] Further, in step (2), the molar volume ratio of the compound shown in formula (VII), silver nitrate, 2-iodoxybenzoic acid, tetrabutylammonium bromide, dichloromethane, and trifluoroacetic acid is 1.00 mol: 0.01 mol: 1.10 mol: 0.01 mol: 1.00 L: 0.10 L; the reaction time is 4 h;

[0051] After the reaction is completed, it is also necessary to quench with saturated sodium thiosulfate solution, filter with diatomaceous earth, extract the obtained solution three times with ethyl acetate, dry with anhydrous sodium sulfate, perform vacuum concentration and reduced pressure concentration, and use petroleum ether and ethyl acetate as eluents to obtain the compound shown in formula (VIII) through silica gel column chromatography purification.

[0052] Application of azaphilone compounds, the azaphilone compounds can be used to prepare anti-tumor drugs.

[0053] Application of derivatives of azaphilone compounds, the derivatives of azaphilone compounds can be used to prepare anti-tumor drugs.

[0054] Beneficial effects: 29.1, 29.04, 28.99, 28.5, 22.6, 19.5, 14.1, 7.1.

[0055] Example 2

[0056] In this example, compound S-3 was synthesized on the basis of compound S-2 prepared in Example 1, and the synthesis process is as follows:

[0057] In a dry reaction eggplant-shaped flask under nitrogen protection, silver nitrate (0.01 mol) was added to a dichloromethane (1 L DCM) solution of compound S-2 (1.0 mol), and then trifluoroacetic acid (0.1 L CF3COOH) (DCM:CF3COOH = 10:1) was added dropwise. After stirring at room temperature for 30 min, 2-iodoxybenzoic acid (1.1 mol) and tetrabutylammonium bromide (0.1 mol) were added. The resulting mixture was stirred at room temperature for 4 h. The reaction was quenched with saturated sodium thiosulfate solution, and the insoluble matter was filtered through diatomaceous earth. The obtained solution was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under vacuum, and chromatographed on silica gel (eluted with petroleum ether / ethyl acetate). The obtained mixture was concentrated under reduced pressure and purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound S-3 with a yield of 84%. The reaction route is shown below:

[0058]

[0059] 1H NMR data of compound S-3: 1 H NMR(400MHz,CDCl3)δ7.88(s,1H),6.10(s,1H),5.51(s,1H),2.45-2.38(m,2H),1.62(p,J=7.8Hz,2H),1.55(s,3H),1.38-1.24(m,10H),0.92-0.85(m,3H). 13 C NMR(100MHz,CDCl3)δ196.3,195.8,163.1,152.9,144.1,115.8,108.3,104.9,83.4,33.2,31.7,29.1,29.0,28.9,28.5,26.4,22.6,14.1。

[0060] Example 3

[0061] Based on the compound S-3 provided in Example 2, compounds 1a-1c were synthesized in this example. The structural formulas of compounds 1a-1c are shown below:

[0062]

[0063] The specific synthesis process of the compound is as follows:

[0064] 1. The synthesis process of compound 1a includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, N-chlorosuccinimide (1.2 mol) was added to a CH3CN (2 L) solution of compound S-3 (1.0 mol). The resulting mixture was stirred at room temperature for 24 h, and the reaction solution was directly concentrated under vacuum. The residue was chromatographed on silica gel (eluted with petroleum ether / ethyl acetate), and the resulting mixture was concentrated under reduced pressure. The product 1a was purified by silica gel column chromatography using petroleum ether and ethyl acetate as the eluent, with a yield of 84%. The reaction route is as follows:

[0065]

[0066] The NMR data of compound 1a: 1 H NMR(400MHz,CDCl3)δ7.92(s,1H),6.56(s,1H),3.89(s,1H),2.51(t,J=7.6,2H),1.67(p,J=7.6Hz,2H),1.57(s,3H),1.44 - 1.28(m,10H),0.88(t,J=6.8,3H). 13 C NMR(100MHz,CDCl3)δ194.0,189.9,165.1,152.2,139.8,115.4,108.4,105.5,84.0,33.6,31.7,29.1,29.0,28.9,28.6,26.6,22.6,14.1。

[0067] 2. The synthesis process of compound 1b includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, N-bromosuccinimide (1.2 mol) was added to a CH3CN (2 L) solution of compound S-3 (1.0 mol). The resulting mixture was stirred at room temperature for 6 h, and the reaction solution was directly concentrated under vacuum. The residue was chromatographed on silica gel (eluted with petroleum ether / ethyl acetate), and the resulting mixture was concentrated under reduced pressure. The product 1b was purified by silica gel column chromatography using petroleum ether and ethyl acetate as the eluent, with a yield of 86%. The reaction route is as follows:

[0068]

[0069] The NMR data of compound 1b: 1 H NMR(400MHz,CDCl3)δ7.90(s,1H),6.61(s,1H),3.49(s,1H),2.56 - 2.49(m,2H),1.71 - 1.64(m,2H),1.58(s,3H),1.39 - 1.28(m,10H),0.89 - 0.87(m,3H). 1313C NMR (100 MHz, CDCl3) δ 194.4, 190.4, 165.6, 152.4, 142.2, 116.3, 108.3, 100.1, 84.1, 33.7, 31.9, 29.3, 29.2, 29.1, 28.7, 26.7, 22.7, 14.2.

[0070] 3. The synthesis process of compound 1c includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, N-iodosuccinimide (1.2 mol) was added to a CH3CN (2 L) solution of compound S-3 (1.0 mol). The resulting mixture was stirred at room temperature for 3 h. The reaction solution was directly concentrated under vacuum. The residue was chromatographed on silica gel (eluted with petroleum ether / ethyl acetate), and the resulting mixture was concentrated under reduced pressure. Using petroleum ether and ethyl acetate as eluents, silica gel column chromatography was used to purify the product 1c with a yield of 87%. The reaction route is as follows:

[0071]

[0072] NMR data of compound 1c: 1 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 6.59 (s, 1H), 2.57 - 2.46 (m, 2H), 1.67 (p, J = 6.8 Hz, 3H), 1.55 (s, 3H), 1.40 - 1.27 (m, 10H), 0.88 (t, J = 6.0 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 194.5, 192.0, 165.9, 152.2, 146.1, 117.0, 113.1, 83.3, 78.6, 33.5, 31.7, 29.1, 29.0, 28.9, 28.7, 26.6, 22.5, 14.1.

[0073] Example 4

[0074] The structural formulas of a series of novel-structured Azaphilone compounds 2a - 2k synthesized in this example are as follows:

[0075]

[0076] 1. The synthesis process of compound 2a is as follows: The reaction route is shown below. In a dry reaction eggplant-shaped flask, molecular sieve and compound B1 (1.5 mol) are added to a toluene (3 L) solution of compound S-3 (1.0 mol). Stir at room temperature for 10 min, then stir the resulting mixture at 110 °C for 1 h. Then add triethylamine (2.0 mol) and continue heating and stirring for 1 h. Quench the reaction solution with 1 M HCl. Extract the obtained solution three times with ethyl acetate, dry over anhydrous sodium sulfate, concentrate in vacuo, perform chromatographic analysis on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the obtained mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 2a with a yield of 71%. The reaction route is shown below:

[0077]

[0078] 1H NMR data of compound 2a: 1 H NMR(400MHz,CDCl3)δ8.79(s,1H),6.07(s,1H),5.27(s,1H),2.58(s,3H),2.46-2.37(m,2H),1.68(s,3H),1.62(p,J=7.6Hz,2H),1.39-1.25(m,10H),0.90-0.84(m,3H). 13 C NMR(100MHz,CDCl3)δ194.4,190.2,168.3,165.7,162.6,153.7,144.2,123.3,111.1,107.7,104.9,87.7,31.8,30.1,29.2,29.1,29.0,26.5,26.3,22.6,14.1。

[0079] 2. The synthesis process of compound 2b is as follows: The reaction route is shown below. In a dry reaction eggplant-shaped flask, molecular sieve and compound B2 (1.5 mol) are added to a toluene (3 L) solution of compound S-3 (1.0 mol). Stir at room temperature for 10 min, then stir the resulting mixture at 110 °C for 1 h. Then add triethylamine (2.0 mol) and continue heating and stirring for 1 h. Quench the reaction solution with 1 M HCl. Extract the obtained solution three times with ethyl acetate, dry over anhydrous sodium sulfate, concentrate in vacuo, perform chromatographic analysis on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the obtained mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 2b with a yield of 75%. The reaction route is shown below:

[0080]

[0081] 1H NMR data of compound 2b:1 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 6.06 (s, 1H), 5.26 (s, 1H), 3.25 (dq, J = 20.4, 7.2 Hz, 1H), 2.78 (dq, J = 20.0, 6.8 Hz, 1H), 2.41 (t, J = 7.6 Hz, 2H), 1.67 (s, 3H), 1.65 - 1.56 (m, 2H), 1.37 - 1.25 (m, 10H), 1.08 (t, J = 7.2 Hz, 3H), 0.86 (t, J = 6.8 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 197.4, 190.3, 168.1, 165.4, 162.5, 153.5, 144.3, 123.3, 111.1, 107.7, 104.9, 87.6, 35.6, 33.2, 31.7, 29.1, 29.0, 28.9, 26.4, 26.2, 22.6, 14.0, 7.2。

[0082] 3. The synthesis process of compound 2c includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, molecular sieve and compound B3 (1.5 mol) are added to the toluene (3 L) solution of compound S-3 (1.0 mol). Stir at room temperature for 10 min, then stir the resulting mixture at 110 °C for 1 h, then add diisopropylethylamine (2.0 mol), continue heating and stirring for 1 h. Quench the reaction solution with 1 M HCl. Extract the obtained solution with ethyl acetate three times, dry over anhydrous sodium sulfate, concentrate under vacuum, perform chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the obtained mixture under reduced pressure. Purify by silica gel column chromatography with petroleum ether and ethyl acetate as the eluent to obtain compound 2c with a yield of 55%. The reaction route is as follows:

[0083]

[0084] NMR data of compound 2c: 1 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 6.58 - 6.50 (m, 1H), 6.05 (s, 1H), 5.30 (s, 1H), 2.43 - 2.37 (m, 2H), 1.89 (d, J = 6.8 Hz, 3H), 1.87 (s, 3H), 1.69 (s, 3H), 1.65 - 1.57 (m, 2H), 1.32 (m, 10H), 0.90 - 0.86 (m, 3H). 1313C NMR (100 MHz, CDCl3) δ 190.7, 190.6, 167.8, 162.8, 161.2, 149.9, 146.3, 143.9, 137.6, 125.4, 111.6, 107.3, 105.3, 87.7, 33.3, 31.7, 29.1, 29.0, 28.9, 26.5, 25.6, 22.6, 15.4, 14.0, 10.8。

[0085] 4. The synthesis process of compound 2d includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, molecular sieve and compound B4 (1.5 mol) are added to a toluene (3 L) solution of compound S-3 (1.0 mol). Stir at room temperature for 10 min, then stir the resulting mixture at 110 °C for 1 h. Then add triethylamine (2.0 mol) and continue heating and stirring for 1 h. Quench the reaction solution with 1 M HCl. Extract the obtained solution three times with ethyl acetate, dry over anhydrous sodium sulfate, concentrate under vacuum, perform column chromatography on the residue on silica gel (elute with petroleum ether / ethyl acetate), and concentrate the obtained mixture under reduced pressure. Purify by silica gel column chromatography with petroleum ether and ethyl acetate as the eluent to obtain compound 2d with a yield of 60%. The reaction route is as follows:

[0086]

[0087] 1H NMR data of compound 2d: 1 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.82 - 7.80 (m, 2H), 7.61 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 6.07 (s, 1H), 5.34 (s, 1H), 2.41 - 2.37 (m, 2H), 1.75 (s, 3H), 1.63 - 1.55 (m, 2H), 1.38 - 1.25 (m, 10H), 0.88 - 0.85 (m, 3H). 13 13C NMR (100 MHz, CDCl3) δ 190.5, 188.9, 167.7, 164.1, 162.8, 150.8, 144.0, 135.4, 134.5, 129.9, 128.6, 124.6, 111.6, 107.4, 105.2, 88.2, 33.3, 31.7, 29.1, 29.0, 28.9, 26.5, 25.8, 22.6, 14.0。

[0088] 5. The synthesis process of compound 2e includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, molecular sieve and compound B1 (1.5 mol) are added to a toluene (3 L) solution of compound 1a (1.0 mol). Stir at room temperature for 10 min, then stir the resulting mixture at 110 °C for 1 h, then add triethylamine (2.0 mol), continue heating and stirring for 1 h. Quench the reaction solution with 1 M HCl. Extract the resulting solution three times with ethyl acetate, dry over anhydrous sodium sulfate, concentrate under vacuum, perform chromatographic analysis on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 2e with a yield of 57%. The reaction route is as follows:

[0089]

[0090] 1H NMR data of compound 2e: 1 H NMR(400MHz,CDCl3)δ8.81(s,1H),6.55(s,1H),2.59(s,3H),2.52(t,J=7.6Hz,2H),1.74-1.62(m,5H),1.43-1.26(m,10H),0.91-0.85(m,3H). 13 13C NMR(100MHz,CDCl3)δ194.2,183.5,167.7,164.7,163.7,163.7,152.6,139.4,123.9,110.5,108.3,105.2,87.6,33.6,31.7,30.1,29.1,29.02,28.95,26.6,26.1,22.6,14.12。

[0091] 6. The synthesis process of compound 2f includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, molecular sieve and compound B3 (1.5 mol) are added to a toluene (3 L) solution of compound 1c (1.0 mol). Stir at room temperature for 10 min, then stir the resulting mixture at 110 °C for 1 h, then add triethylamine (2.0 mol), continue heating and stirring for 1 h. Quench the reaction solution with 1 M HCl. Extract the resulting solution three times with ethyl acetate, dry over anhydrous sodium sulfate, concentrate under vacuum, perform chromatographic analysis on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 2f with a yield of 70%. The reaction route is as follows:

[0092]

[0093] 1H NMR data of compound 2f: 11H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 6.61 (s, 1H), 3.27 (dq, J = 19.6, 7.2 Hz, 1H), 2.78 (dq, J = 19.6, 7.2 Hz, 1H), 2.54 (t, J = 7.6, 2H), 1.74 - 1.66 (m, 5H), 1.46 - 1.28 (m, 10H), 1.10 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 6.8 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 197.4, 185.3, 167.7, 165.3, 163.9, 152.3, 145.5, 123.7, 112.9, 112.5, 86.8, 79.7, 35.7, 33.6, 31.8, 29.15, 29.06, 29.0, 26.7, 26.1, 22.6, 14.1, 7.2。

[0094] 7. The synthesis process of compound 2g includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, molecular sieve and compound B3 (1.5 mol) are added to the toluene (3 L) solution of compound 1a (1.0 mol). Stir at room temperature for 10 min, then stir the obtained mixture at 110 °C for 1 h, then add diisopropylethylamine (2.0 mol), continue heating and stirring for 1 h. Quench the reaction solution with 1 M HCl. Extract the obtained solution with ethyl acetate three times, dry over anhydrous sodium sulfate, concentrate under vacuum, perform chromatography on the residue on silica gel (elute with petroleum ether / ethyl acetate), and concentrate the obtained mixture under reduced pressure. Purify by silica gel column chromatography with petroleum ether and ethyl acetate as the eluent to obtain compound 2g with a yield of 59%. The reaction route is as follows:

[0095]

[0096] NMR data of compound 2g: 1 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 6.57 - 6.50 (m, 2H), 2.53 - 2.46 (m, 2H), 1.90 (d, J = 7.2 Hz, 3H), 1.87 (s, 3H), 1.71 (s, 3H), 1.70 - 1.62 (m, 2H), 1.42 - 1.28 (m, 10H), 0.90 - 0.86 (m, 3H). 1313C NMR (100 MHz, CDCl3) δ 188.7, 183.9, 167.2, 165.1, 162.1, 149.8, 141.4, 135.3, 134.7, 129.9, 128.7, 125.3, 111.8, 107.7, 100.6, 88.0, 33.7, 31.7, 29.1, 29.0, 28.9, 26.6, 25.7, 22.6, 14.0.

[0097] 8. The synthesis process of compound 2h includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, molecular sieve and compound B4 (1.5 mol) are added to a toluene (3 L) solution of compound 1b (1.0 mol). The mixture is stirred at room temperature for 10 min, and then the resulting mixture is stirred at 110 °C for 1 h. Then, triethylamine (2.0 mol) is added, and stirring is continued while heating for 1 h. The reaction solution is quenched with 1 M HCl. The obtained solution is extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under vacuum, and the residue is chromatographed on silica gel (eluted with petroleum ether / ethyl acetate). The obtained mixture is concentrated under reduced pressure. Using petroleum ether and ethyl acetate as eluents, compound 2h is purified by silica gel column chromatography with a yield of 68%. The reaction route is as follows:

[0098]

[0099] 1H NMR data of compound 2h: 1 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.80 (d, J = 7.2 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 6.59 (s, 1H), 2.55 - 2.44 (m, 2H), 1.77 (s, 3H), 1.65 (p, J = 7.6 Hz, 2H), 1.40 - 1.26 (m, 10H), 0.87 (t, J = 6.8 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 188.7, 183.9, 167.2, 165.1, 162.1, 149.8, 141.4, 135.3, 134.7, 129.9, 128.7, 125.3, 111.8, 107.7, 100.6, 88.0, 33.7, 31.7, 29.1, 29.0, 28.9, 26.6, 25.7, 22.6, 14.0.

[0100] 9. The synthesis process of compound 2i includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, molecular sieve and compound B5 (1.5 mol) are added to the toluene (3 L) solution of compound 1a (1.0 mol). Stir at room temperature for 10 min, then stir the resulting mixture at 110 °C for 1 h, then add triethylamine (2.0 mol), continue heating and stirring for 1 h. Quench the reaction solution with 1 M HCl. Extract the obtained solution with ethyl acetate three times, dry over anhydrous sodium sulfate, concentrate under vacuum, perform chromatographic analysis on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the obtained mixture under reduced pressure. Purify by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain compound 2i with a yield of 48%. The reaction route is as follows:

[0101]

[0102] 1H NMR data of compound 2i: 1 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.69 (dd, J = 1.6, 0.8 Hz, 1H), 7.38 (d, J = 3.6 Hz, 1H), 6.60 (dd, J = 3.6, 1.6 Hz, 1H), 6.53 (s, 1H), 2.55 - 2.45 (m, 2H), 1.76 (s, 3H), 1.68 - 1.63 (m, 2H), 1.27 - 1.18 (s, 10H), 0.88 (t, J = 6.4 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 183.7, 179.7, 167.3, 165.0, 162.3, 150.5, 142.3, 139.5, 137.0, 136.9, 129.0, 124.9, 111.0, 108.6, 105.2, 88.1, 33.8, 31.8, 29.2, 29.1, 29.0, 26.7, 25.8, 22.7, 14.2.

[0103] 10. The synthesis process of compound 2j includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, molecular sieve and compound B5 (1.5 mol) are added to the toluene (3 L) solution of compound 1b (1.0 mol). Stir at room temperature for 10 min, then stir the resulting mixture at 110 °C for 1 h, then add triethylamine (2.0 mol), continue heating and stirring for 1 h. Quench the reaction solution with 1 M HCl. Extract the obtained solution with ethyl acetate three times, dry over anhydrous sodium sulfate, concentrate under vacuum, perform chromatographic analysis on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the obtained mixture under reduced pressure. Purify by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain compound 2j with a yield of 46%. The reaction route is as follows:

[0104]

[0105] 1H NMR data of compound 2j: 1 H NMR(400MHz,CDCl3)δ8.38(s,1H),7.78(d,J=4.8Hz,1H),7.72(d,J=4.0Hz,1H),7.15(t,J=4.4Hz,1H),6.58(s,1H),2.55-2.45(m,2H),1.76(s,3H),1.65(p,J=7.2Hz,2H),1.42-1.28(m,10H),0.87(t,J=6.8Hz,4H). 13 C NMR(100MHz,CDCl3)δ183.8,179.6,167.2,165.1,162.3,150.3,142.2,141.5,136.9,136.8,128.9,124.8,111.7,107.7,100.4,87.9,33.7,31.7,29.1,29.0,28.9,26.6,25.7,22.6,14.0。

[0106] 11. The synthesis process of compound 2k includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, molecular sieve and compound B6 (1.5 mol) are added to the toluene (3 L) solution of compound 1a (1.0 mol), and the mixture is stirred at room temperature for 10 min. Then the obtained mixture is stirred at 110 °C for 1 h, then triethylamine (2.0 mol) is added, and stirring is continued for 1 h. The reaction solution is quenched with 1 M HCl, and the resulting solution is extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under vacuum, chromatographed on silica gel (eluted with petroleum ether / ethyl acetate), and the obtained mixture is concentrated under reduced pressure. Purified by silica gel column chromatography with petroleum ether and ethyl acetate as the eluent to obtain compound 2k with a yield of 53%. The reaction route is as follows:

[0107]

[0108] 1H NMR data of compound 2k: 1 H NMR(400MHz,CDCl3)δ8.44(s,1H),7.73-7.58(m,1H),7.34(d,J=3.6Hz,1H),6.57(dd,J=3.6,1.6Hz,1H),6.51(s,1H),2.53-2.41(m,2H),1.72(s,3H),1.63(p,J=7.6Hz,2H),1.35-1.24(m,10H),0.84(t,J=6.8Hz,3H).13 13C NMR (100 MHz, CDCl3) δ 183.5, 174.0, 166.8, 164.8, 162.9, 151.1, 150.5, 148.6, 139.3, 124.4, 123.0, 113.1, 110.8, 108.4, 105.0, 88.0, 33.6, 31.6, 29.0, 28.92, 28.85, 26.5, 25.6, 22.5, 14.0.

[0109] Example 5

[0110] The structural formula of the derivative synthesized on the basis of a series of structurally novel Azaphilone compounds provided in Example 4 above is as follows:

[0111]

[0112] 1. The synthesis process of compound 3a includes: The reaction route is as shown below. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound a (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, chromatograph the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as the eluent to obtain compound 3a with a yield of 79%. The reaction route is as shown below:

[0113]

[0114] NMR data of compound 3a: 1 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 6.66 (s, 1H), 6.54 (q, J = 6.8 Hz, 1H), 3.80 (t, J = 7.6 Hz, 2H), 2.61 - 2.48 (m, 2H), 1.86 (d, J = 7.6 Hz, 3H), 1.84 (s, 3H), 1.77 - 1.72 (m, 2H), 1.70 - 1.62 (m, 5H), 1.47 - 1.39 (m, 2H), 1.40 - 1.25 (m, 18H), 0.88 (t, J = 6.8 Hz, 6H). 1313C NMR (100 MHz, CDCl3) δ 191.2, 181.5, 168.2, 164.3, 150.7, 146.2, 144.6, 138.2, 137.4, 124.7, 112.1, 111.9, 99.7, 88.7, 53.3, 32.2, 31.7, 31.6, 30.8, 29.3, 29.1, 29.05, 29.04, 28.97, 28.6, 26.4, 26.2, 22.6, 22.5, 15.3, 14.02, 14.00, 10.9。

[0115] 2. The synthesis process of compound 3b includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound b (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, and perform chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate). The resulting mixture is concentrated under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3b with a yield of 78%. The reaction route is as follows:

[0116]

[0117] 1H NMR data of compound 3b: 1 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 6.76 - 6.55 (m, 2H), 4.03 (hept, J = 7.2 Hz, 2H), 3.40 (dt, J = 9.2, 5.6 Hz, 3H), 2.78 - 2.63 (m, 2H), 1.83 - 1.81 (m, 6H), 1.79 - 1.73 (m, 2H), 1.62 - 1.55 (m, 5H), 1.40 - 1.23 (m, 10H), 0.85 (t, J = 6.8 Hz, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 190.2, 179.4, 168.0, 162.2, 152.9, 146.6, 144.7, 139.1, 137.1, 122.9, 110.9, 110.8, 96.9, 88.3, 56.9, 49.8, 33.1, 31.3, 31.1, 28.7, 28.6, 28.1, 26.2, 22.1, 15.3, 14.0, 10.5。

[0118] 3. The synthesis process of compound 3c is as follows: The reaction route is shown below. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound c (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform chromatographic analysis of the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3c with a yield of 74%. The reaction route is shown below:

[0119]

[0120] 1H NMR data of compound 3c: 1 H NMR(400MHz,DMSO-d6)δ7.94(s,1H),6.74-6.68(m,2H),5.28(t,J=4.8Hz,1H),5.10(t,J=4.8Hz,1H),4.37(p,J=5.6Hz,1H),3.73-3.65(m,3H),3.57-3.49(m,1H),2.73(t,J=8,2H),1.85(d,J=6.8Hz,3H),1.78(s,3H),1.65-1.55(m,5H),1.41-1.23(m,10H),0.85(t,J=6.8Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ190.3,179.6,168.0,161.9,153.7,147.1,144.3,137.5,136.1,123.0,110.9,110.7,96.9,88.2,63.1,60.2,60.1,31.8,31.2,28.6,28.5,27.8,26.4,22.1,15.2,13.9,10.3。

[0121] 4. The synthesis process of compound 3d is as follows: The reaction route is shown below. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound d (1.0 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform chromatographic analysis of the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3d with a yield of 75%. The reaction route is shown below:

[0122]

[0123] 1H NMR data of compound 3d: 11H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 6.66 (s, 1H), 6.54 (q, J = 6.8 Hz, 1H), 3.98 - 3.85 (m, 2H), 2.69 - 2.49 (m, 8H), 1.93 (t, J = 7.2 H), 1.86 (d, J = 6.8 Hz, 3H), 1.83 (s, 3H), 1.70 - 1.61 (m, 5H), 1.46 - 1.27 (m, 10H), 1.04 (t, J = 7.2 Hz, 6H), 0.89 - 0.86 (m, 3H). 13 13C NMR (100 MHz, CDCl3) δ 191.1, 181.5, 168.3, 164.5, 151.1, 146.2, 144.7, 138.3, 137.4, 124.6, 112.2, 111.8, 99.6, 88.7, 51.1, 48.8, 46.1, 32.1, 31.7, 29.7, 29.3, 29.2, 29.1, 28.7, 28.1, 26.3, 22.6, 15.4, 14.1, 10.9, 10.8。

[0124] 5. The synthesis process of compound 3e includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound e (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, and perform column chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate). The resulting mixture is concentrated under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3e with a yield of 74%. The reaction route is as follows:

[0125]

[0126] NMR data of compound 3e: 1 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 6.64 (s, 1H), 6.54 (q, J = 6.8 Hz, 1H), 3.90 (m, 1H), 2.59 (t, J = 8.0 Hz, 2H), 2.07 - 1.96 (m, 4H), 1.86 (d, J = 9.6 Hz, 3H), 1.84 (s, 3H), 1.68 (s, 3H), 1.64 - 1.58 (m, 2H), 1.50 - 1.26 (m, 14H), 0.90 - 0.84 (t, J = 6.8, 3H). 1313C NMR (100 MHz, CDCl3) δ 191.2, 181.6, 168.4, 164.8, 150.6, 146.1, 144.4, 137.4, 134.6, 124.6, 112.4, 112.1, 99.4, 88.8, 60.3, 33.8, 32.8, 32.4, 31.7, 29.2, 29.1, 29.0, 28.8, 26.4, 25.7, 24.7, 22.6, 15.3, 14.0, 10.9.

[0127] 6. The synthesis process of compound 3f includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound f (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, and perform column chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate). The resulting mixture is concentrated under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3f with a yield of 76%. The reaction route is as follows:

[0128]

[0129] 1H NMR data of compound 3f: 1 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 6.67 (s, 1H), 6.53 (q, J = 6.8 Hz, 1H), 3.90 (dtd, J = 20.8, 14.8, 6.0 Hz, 2H), 3.68 (t, J = 4.4, 4H), 2.67 (t, J = 6.0 Hz, 2H), 2.62 - 2.52 (m, 4H), 2.51 - 2.42 (m, 2H), 1.90 - 1.82 (m, 6H), 1.70 - 1.63 (m, 5H), 1.47 - 1.28 (m, 10H), 0.88 (t, J = 13.6 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 191.1, 181.7, 168.3, 164.5, 150.5, 146.0, 144.6, 139.3, 137.4, 124.5, 111.8, 111.6, 99.9, 88.6, 66.7, 58.2, 53.8, 50.2, 32.3, 31.7, 29.3, 29.2, 29.1, 28.5, 26.4, 22.6, 15.3, 14.1, 11.0.

[0130] 7. The synthesis process of compound 3g is as follows: The reaction route is shown below. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound g (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform chromatography analysis on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as the eluent to obtain compound 3g with a yield of 73%. The reaction route is shown below:

[0131]

[0132] The NMR data of compound 3g: 1 H NMR(400MHz,CDCl3)δ7.91(s,1H),7.44-7.39(m,3H),7.11(d,J=7.6Hz,2H),6.70(s,1H),6.55(q,J=7.2Hz,1H),5.03(s,2H),2.52(t,J=8,2H),1.87(d,J=3.6Hz,3H),1.76(s,3H),1.70(s,3H),1.61(p,J=7.6Hz,2H),1.40-1.25(m,10H),0.87(t,J=6.8,3H). 13 C NMR(100MHz,CDCl3)δ191.0,181.8,168.1,163.6,151.1,146.5,144.5,138.7,137.5,134.1,129.6,129.0,126.4,124.9,111.9,100.4,88.7,56.7,32.3,31.7,29.2,29.1,29.0,28.4,26.2,22.6,15.4,14.1,10.7。

[0133] 8. The synthesis process of compound 3h is as follows: The reaction route is shown below. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound h (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform chromatography analysis on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as the eluent to obtain compound 3h with a yield of 75%. The reaction route is shown below:

[0134]

[0135] The NMR data of compound 3h: 11H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.44 (d, J = 1.6, 1H), 6.65 (s, 1H), 6.51 (q, J = 6.8 Hz, 1H), 6.48 (d, J = 3.2 Hz, 1H), 6.42 (t, J = 2.6 Hz, 1H), 4.96 (s, 2H), 2.70 (t, J = 7.8 Hz, 2H), 1.85 (d, J = 6.8 Hz, 3H), 1.81 (s, 3H), 1.72 - 1.64 (m, 5H), 1.48 - 1.25 (m, 10H), 0.88 (t, J = 6.8 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 190.9, 181.9, 168.2, 163.5, 150.7, 146.7, 146.5, 144.4, 144.1, 137.9, 137.4, 124.9, 112.2, 111.6, 111.0, 100.4, 88.6, 49.0, 32.3, 31.7, 29.2, 29.1, 28.3, 26.2, 22.6, 15.4, 14.1, 10.7。

[0136] 9. The synthesis process of compound 3i includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound i (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, and perform chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate). The resulting mixture is concentrated under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as the eluent to obtain compound 3i with a yield of 77%. The reaction route is as follows:

[0137]

[0138] NMR data of compound 3i: 1 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.42 - 7.32 (m, 1H), 7.06 - 7.03 (m, 2H), 6.66 (s, 1H), 6.52 (q, J = 8.0 Hz, 1H), 5.17 (s, 2H), 2.77 - 2.57 (m, 2H), 1.84 (d, J = 7.2 Hz, 3H), 1.78 (s, 3H), 1.71 - 1.61 (m, 5H), 1.42 (p, J = 7.0 Hz, 2H), 1.70 - 1.62 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H). 1313C NMR (100 MHz, CDCl3) δ 190.9, 181.8, 168.1, 163.2, 150.6, 146.4, 144.3, 137.8, 137.5, 136.0, 127.7, 127.6, 127.1, 124.9, 112.2, 111.7, 100.5, 88.6, 51.4, 32.3, 31.7, 29.2, 29.1, 29.0, 28.4, 26.1, 22.5, 15.3, 14.0, 10.7。

[0139] 10. The synthesis process of compound 3j includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound j (1.2 mol) are added to a solution of compound 2e (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, and perform chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate). The resulting mixture is concentrated under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3j with a yield of 73%. The reaction route is as follows:

[0140]

[0141] 1H NMR data of compound 3j: 1 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.56 (d, J = 4.8 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.22 - 7.13 (m, 2H), 6.63 (s, 1H), 4.49 - 4.31 (m, 2H), 3.32 (hept, J = 8.0, 7.6 Hz, 2H), 2.61 - 2.52 (m, 5H), 1.69 - 1.59 (m, 5H), 1.47 - 1.26 (m, 10H), 0.90 - 0.85 (m, 3H). 13 13C NMR (100 MHz, CDCl3) δ 194.5, 181.4, 169.2, 168.8, 155.7, 151.0, 149.8, 144.8, 141.8, 137.0, 123.8, 122.4, 122.0, 112.1, 111.3, 99.5, 88.6, 52.2, 38.4, 32.1, 31.7, 30.2, 29.2, 29.1, 29.0, 28.5, 27.2, 22.6, 14.1。

[0142] 11. The synthesis process of compound 3k is as follows: The reaction route is shown below. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound j (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform chromatographic analysis on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as the eluent to obtain compound 3k with a yield of 74%. The reaction route is shown below:

[0143]

[0144] The NMR data of compound 3k: 1 H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 4.8 Hz, 1H), 7.90 (s, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.20 (t, J = 6.4 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.62 (s, 1H), 6.52 (q, J = 7.2 Hz, 1H), 4.38 - 4.25 (m, 2H), 3.23 (h, J = 5.6 Hz, 2H), 2.56 (t, J = 7.2, 2H), 1.88 - 1.85 (m, 6H), 1.70 - 1.60 (m, 5H), 1.45 - 1.27 (m, 10H), 0.90 - 0.86 (m, 3H). 13 C NMR (100 MHz, CDCl3) δ 191.2, 181.7, 168.4, 164.5, 155.7, 151.2, 150.0, 146.2, 144.7, 138.2, 137.5, 137.1, 124.7, 123.8, 122.6, 112.2, 111.8, 99.9, 88.8, 52.1, 38.5, 32.3, 31.9, 29.4, 29.3, 29.2, 28.7, 26.4, 22.7, 15.5, 14.2, 11.1.

[0145] 12. The synthesis process of compound 3l is as follows: The reaction route is shown below. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound l (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform chromatographic analysis on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as the eluent to obtain compound 3l with a yield of 74%. The reaction route is shown below:

[0146]

[0147] 1H NMR data of Compound 3l: 1 H NMR(400MHz,CDCl3)δ7.89(s,1H),7.39(d,J=8.4Hz,2H),7.07(d,J=8.4Hz,2H),6.68(s,1H),6.53(q,J=6.8,1H),5.01(s,2H),2.55-2.48(m,2H),1.86(d,J=7.6Hz,3H),1.75(s,3H),1.68(s,3H),1.65-1.58(m,2H),1.40-1.33(m,2H),1.32-1.25(m,8H),0.87(t,J=6.8Hz,3H). 13 C NMR(100MHz,CDCl3)δ181.9,168.1,163.5,150.8,146.4,144.2,138.5,137.5,135.1,132.6,129.8,127.9,124.9,112.1,111.8,100.6,88.6,55.8,32.3,31.7,29.15,29.08,29.0,28.3,26.2,22.5,15.4,14.0,10.7。

[0148] 13. The synthesis process of Compound 3m includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and Compound m (1.2 mol) are added to a solution of Compound 2e (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography with petroleum ether and ethyl acetate as the eluent to obtain Compound 3m with a yield of 72%. The reaction route is as follows:

[0149]

[0150] 1H NMR data of Compound 3m: 1 H NMR(400MHz,CDCl3)δ8.85(s,1H),7.71(d,J=8.0Hz,2H),7.45-7.32(m,2H),6.72(s,1H),5.22(s,2H),2.55-1.47(m,5H),1.70(s,3H),1.61(p,J=8.0,7.6Hz,2H),1.36-1.24(m,10H),0.86(t,J=6.8Hz,3H). 1313C NMR (100 MHz, CDCl3) δ 194.6, 181.8, 168.8, 168.6, 150.5, 144.4, 142.8, 138.3, 134 (d, J = 33 Hz), 126.8, 126.6 (q, J = 3.8 Hz), 124.9, 122.2, 112.4, 111.3, 100.7, 88.6, 56.5, 32.2, 31.7, 30.2, 29.10, 29.08, 29.0, 28.3, 27.1, 22.5, 14.0。

[0151] 14. The synthesis process of compound 3n includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound n (1.0 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, and perform chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate). The resulting mixture is concentrated under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3n with a yield of 78%. The reaction route is as follows:

[0152]

[0153] 13C NMR data of compound 3n: 1 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.27 (s, 1H), 7.25 (s, 1H), 6.70 (s, 1H), 6.54 (q, J = 7.2 Hz, 1H), 5.11 (s, 2H), 2.54 - 2.45 (m, 2H), 1.90 - 1.84 (m, 3H), 1.73 (s, 3H), 1.69 (s, 3H), 1.62 (m, 2H), 1.41 - 1.23 (m, 10H), 0.89 - 0.84 (m, 3H). 13 13C NMR (100 MHz, CDCl3) δ 191.0, 182.1, 168.2, 163.7, 150.9, 146.8, 144.4, 138.8, 138.3, 137.5, 128.8, 126.9, 126.7 (q, J = 3.9 Hz), 125.1, 112.4, 112.0, 101.0, 100.0, 88.7, 56.0, 32.5, 31.8, 29.3, 29.2, 29.1, 28.5, 26.3, 22.7, 15.5, 14.2, 10.8。

[0154] 15. The synthesis process of compound 3o is as follows: The reaction route is shown below. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound o (1.2 mol) are added to a solution of compound 2e (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform chromatographic analysis of the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3o with a yield of 73%. The reaction route is shown below:

[0155]

[0156] 1H NMR data of compound 3o: 1 H NMR(400MHz,CDCl3)δ8.84(s,1H),7.29(s,4H),6.72(s,1H),5.16(s,2H),2.61 - 2.45(m,5H),1.70(s,3H),1.61(p,J=8.0,7.6Hz,2H),1.42 - 1.32(m,2H),1.30 - 1.25(m,8H),0.86(t,J=6.8Hz,3H). 13 C NMR(100MHz,CDCl3)δ194.7,181.9,169.0,168.8,150.9,149.6,144.7,142.9,132.9,128.3,122.3,122.1,120.4(d,J=57.2Hz),112.6,111.4,100.5,88.8,56.5,32.3,31.8,30.4,29.3,29.2,29.1,28.5,27.3,22.7,14.2。

[0157] 16. The synthesis process of compound 3p is as follows: The reaction route is shown below. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound o (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform chromatographic analysis of the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3p with a yield of 74%. The reaction route is shown below:

[0158]

[0159] 1H NMR data of compound 3p: 11H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.34 - 7.26 (m, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.70 (s, 1H), 6.54 (q, J = 6.8 Hz, 1H), 5.06 (s, 2H), 2.58 - 2.47 (m, 2H), 1.86 (d, J = 6.8 Hz, 3H), 1.74 (s, 3H), 1.68 (s, 3H), 1.62 (p, J = 7.6 Hz, 2H), 1.40 - 1.25 (m, 10H), 0.88 - 0.85 (m, 3H). 13 13C NMR (100 MHz, CDCl3) δ 190.9, 181.9, 168.1, 163.6, 150.8, 149.5, 146.6, 144.3, 138.6, 137.4, 132.7, 129.2, 128.1, 124.9, 121.9, 112.2, 111.9, 100.6, 88.6, 55.7, 32.3, 31.7, 29.2, 29.1, 29.0, 28.4, 26.2, 22.5, 15.4, 14.0, 10.6。

[0160] 17. The synthesis process of compound 3q includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound q (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, and perform chromatographic analysis of the residue on silica gel (eluted with petroleum ether / ethyl acetate). The resulting mixture is concentrated under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as the eluent to obtain compound 3q with a yield of 76%. The reaction route is as follows:

[0161]

[0162] 1H NMR data of compound 3q: 11H NMR (400 MHz, CDCl3) δ 9.02 (brs, 1H), 7.76 (s, 1H), 7.44 - 7.41 (m, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 7.01 (s, 1H), 6.60 (s, 1H), 6.50 (t, J = 6.8, 1H), 4.26 - 4.21 (m, 1H), 4.07 - 4.00 (m, 1H)), 3.30 - 3.16 (m, 2H), 2.38 (t, J = 7.8, 2H), 1.85 (d, J = 7.2 Hz, 3H), 1.81 (s, 3H), 1.60 - 1.49 (m, 5H), 1.31 - 1.25 (m, 10H), 0.88 (t, J = 6.8 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 190.8, 181.4, 168.3, 164.5, 151.5, 146.1, 145.0, 138.4, 137.4, 136.3, 126.6, 124.3, 123.3, 122.4, 119.8, 117.3, 112.0, 111.7, 108.8, 99.3, 88.7, 53.9, 32.0, 31.7, 30.9, 29.1, 29.0, 28.4, 26.7, 26.2, 22.6, 15.4, 14.1, 10.9。

[0163] 18. The synthetic process of compound 3r includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound r (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the obtained mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3r with a yield of 74%. The reaction route is as follows:

[0164]

[0165] NMR data of compound 3r: 1 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 7.90 (s,

[0166] 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 6.64 - 6.49 (m, 3H), 6.01 (s, 2H), 4.93 (s, 2H), 2.59 - 2.46 (m, 2H), 1.86 (d, J = 7.6 Hz, 3H), 1.78 (s, 3H), 1.68 (s, 3H), 1.65 - 1.57 (m, 2H), 1.40 - 1.24 (m, 10H), 0.86 (t, J = 6.8 Hz, 3H).

[0167] 1.66 - 1.60 (m, 5H), 1.39 (p, J = 6.4 Hz, 2H), 1.32 - 1.23 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 190.8, 181.6, 168.3, 163.4, 151.8, 146.2, 145.1, 138.6, 137.7, 136.0, 128.4, 126.3, 124.7, 124.4, 120.3, 119.3, 112.6, 112.1, 112.0, 102.2, 99.6, 88.7, 57.5, 32.4, 31.7, 29.2, 29.1, 29.0, 28.4, 26.4, 22.5, 15.3, 14.0, 10.4.

[0169] 19. The synthesis process of compound 3s includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound s (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, and perform column chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate). The resulting mixture is concentrated under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3s with a yield of 76%. The reaction route is as follows:

[0170]

[0171] 1H NMR data of compound 3s: 1 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 6.64 - 6.49 (m, 3H), 6.01 (s, 2H), 4.93 (s, 2H), 2.59 - 2.46 (m, 2H), 1.86 (d, J = 7.6 Hz, 3H), 1.78 (s, 3H), 1.68 (s, 3H), 1.65 - 1.57 (m, 2H), 1.40 - 1.24 (m, 10H), 0.86 (t, J = 6.8 Hz, 3H).

[0172] 1.40 - 1.24 (m, 10H), 0.86 (t, J = 6.8 Hz, 3H). 1313C NMR (100 MHz, CDCl3) δ 191.0, 181.8, 168.1, 163.5, 151.0, 148.8, 148.3, 146.4, 144.4, 138.4, 137.5, 127.4, 124.9, 120.6, 112.0, 111.8, 109.0, 106.9, 101.7, 100.3, 88.6, 56.4, 32.3, 31.7, 29.2, 29.1, 29.0, 28.4, 26.2, 22.6, 15.4, 14.0, 10.6。

[0173] 20. The synthesis process of compound 3t includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound t (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, and perform chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate). The resulting mixture is concentrated under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3t with a yield of 77%. The reaction route is as follows:

[0174]

[0175] 1H NMR data of compound 3t: 1 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 6.66 (s, 1H), 6.54 (q, J = 6.8 Hz, 1H), 4.03 (hept, J = 6.8 Hz, 2H), 2.84 (hept, J = 6.8 Hz, 2H), 2.65 - 2.49 (m, 2H), 2.13 (s, 3H), 1.86 (d, J = 7.2 Hz, 3H), 1.83 (s, 3H), 1.74 - 1.63 (m, 5H), 1.43 (p, J = 6.4 Hz, 2H), 1.38 - 1.24 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H); 13 13C NMR (100 MHz, CDCl3) δ 191.1, 181.7, 168.2, 163.8, 150.4, 146.3, 144.4, 138.5, 137.5, 124.8, 111.8, 100.2, 88.6, 51.8, 34.6, 32.2, 31.7, 29.2, 29.1, 29.0, 28.5, 26.2, 22.5, 16.0, 15.3, 14.0, 10.8。

[0176] 21. The synthesis process of compounds 3u and 3v is as follows: The reaction route is shown below. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound u (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform column chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Using petroleum ether and ethyl acetate as eluents, silica gel column chromatography is used to purify to obtain compounds 3u and 3v. The yield of 3u is 25%, and the yield of 3v is 26%. The reaction route is shown below:

[0177]

[0178] 1H NMR data of compound 3u: 1 H NMR(400MHz,CDCl3)δ8.82(s,1H),6.65(s,1H),5.21(t,J=7.6Hz,1H),3.85(s,3H),3.69(s,3H),2.75-2.65(m,1H),2.65-2.42(m,7H),2.41-2.31(m,1H),1.70(s,3H),1.59(p,J=6.4Hz,2H),1.40(p,J=6.4Hz,2H),1.36-1.23(m,8H),0.86(t,J=6.4Hz,3H). 13 C NMR(100MHz,CDCl3)δ194.5,182.1,172.5,169.3,169.2,168.7,150.5,143.9,139.3,122.1,112.0,111.3,101.0,88.6,53.6,52.1,32.5,31.7,30.2,29.11,29.07,29.0,28.7,28.0,27.0,26.4,22.5,14.0。

[0179] 1H NMR data of compound 3v: 1 H NMR(400MHz,CDCl3)δ8.75(s,1H),6.65(s,1H),5.17-5.06(m,1H),3.86(s,3H),3.70(s,3H),2.76-2.44(m,8H),2.30(dq,J=14.4,7.6Hz,1H),1.69-1.59(m,5H),1.49-1.37(m,2H),1.38-1.23(m,Hz,8H),0.86(t,J=6.4Hz,3H). 1313C NMR (100 MHz, CDCl3) δ 194.3, 181.9, 172.4, 168.6, 168.33, 168.26, 150.6, 143.8, 122.5, 111.9, 111.8, 101.0, 88.5, 53.7, 52.1, 32.5, 31.7, 30.1, 29.2, 29.1, 29.04, 29.00, 28.0, 27.5, 27.1, 22.5, 14.0.

[0180] 22. The synthesis process of compounds 3w and 3x includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound w (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform column chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compounds 3w and 3x. The yield of 3w is 25%, and the yield of 3x is 25%. The reaction route is as follows:

[0181]

[0182] 1H NMR data of compound 3w: 1 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 6.63 (s, 1H), 6.55 (q, J = 6.8 Hz, 1H), 5.12 (t, J = 6.8, 1H), 3.85 (s, 3H), 3.67 (s, 3H), 2.61 - 2.40 (m, 4H), 2.30 - 2.17 (m, 2H), 1.91 - 1.76 (m, 6H), 1.87 (d, J = 6.8, 3H), 1.80 (s, 1H), 1.70 (s, 3H), 1.58 (p, J = 7.6 Hz, 2H), 1.44 - 1.26 (m, 10H), 0.88 - 0.85 (m, 3H). 13 13C NMR (100 MHz, CDCl3) δ 190.8, 182.3, 172.2, 169.0, 168.2, 164.4, 150.8, 146.4, 143.8, 137.4, 135.0, 124.9, 112.1, 111.5, 101.2, 88.6, 53.7, 52.1, 32.5, 31.7, 29.12, 29.06, 29.0, 28.6, 28.0, 26.1, 26.0, 22.6, 15.4, 14.0, 10.8.

[0183] 1H NMR data of compound 3x: 11H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 6.61 (s, 1H), 6.55 (q, J = 6.4 Hz, 1H), 5.06 (t, J = 7.2 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 2.65 - 2.37 (m, 5H), 2.31 - 2.19 (m, 1H), 1.87 (d, J = 6.8 Hz, 3H), 1.83 (s, 3H), 1.69 (s, 3H), 1.59 (p, J = 7.6 Hz, 2H), 1.46 - 1.36 (m, 2H), 1.36 - 1.23 (m, 10H), 0.86 (t, J = 6.4 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 191.0, 182.3, 172.5, 168.4, 168.2, 163.2, 150.8, 146.7, 143.7, 137.6, 135.2, 125.2, 112.4, 111.5, 101.5, 88.6, 53.6, 52.3, 32.7, 31.8, 29.3, 29.24, 29.18, 29.1, 28.2, 27.8, 26.3, 22.7, 15.5, 14.1, 10.8。

[0184] 23. The synthesis process of compound 3y includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound y (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, and perform chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate). The resulting mixture is concentrated under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3y with a yield of 71%. The reaction route is as follows:

[0185]

[0186] NMR data of compound 3y: 1 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 6.66 (s, 1H), 6.55 (q, J = 7.8 Hz, 1H), 4.45 (d, J = 5.2 Hz, 2H), 2.43 (t, J = 8.4 Hz, 2H), 1.86 (d, J = 7.2 Hz, 3H), 1.82 (s, 3H), 1.69 (s, 3H), 1.66 - 1.57 (m, 2H), 1.49 (s, 9H), 1.45 - 1.37 (m, 2H), 1.37 - 1.27 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H). 1313C NMR (100 MHz, CDCl3) δ 191.1, 182.1, 168.1, 165.39, 165.4, 163.6, 150.3, 146.5, 144.3, 139.2, 137.4, 124.8, 111.9, 111.4, 101.0, 88.6, 84.8, 54.4, 32.3, 31.7, 29.13, 29.09, 29.0, 26.2, 22.5, 15.4, 14.0, 10.8。

[0187] 24. The synthesis process of compounds 3z and 3aa includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound z (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform column chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Using petroleum ether and ethyl acetate as eluents, purify by silica gel column chromatography to obtain compounds 3z and 3aa. The yield of 3z is 40%, and the yield of 3aa is 39%. The reaction route is as follows:

[0188]

[0189] 1H NMR data of compound 3z: 1 1H NMR (400 MHz, CDCl3) δ 8.13 - 8.00 (m, 2H), 7.91 (s, 1H), 7.75 - 7.54 (m, 3H), 7.42 (t, J = 8.0 Hz, 2H), 6.86 (s, 1H), 6.57 (q, J = 6.8 Hz, 1H), 2.22 - 2.02 (m, 2H), 1.88 (d, J = 6.8 Hz, 3H), 1.78 (s, 3H), 1.42 (p, J = 7.2 Hz, 2H), 1.25 (s, 3H), 1.24 - 0.94 (m, 10H), 0.82 (t, J = 7.2 Hz, 3H); 13 13C NMR (100 MHz, CDCl3) δ 190.9, 182.3, 168.2, 163.7, 150.4, 144.6, 139.1, 137.6, 136.6, 134.5, 131.2, 129.6, 129.2, 129.0, 127.8, 125.7, 125.1, 125.0, 121.0, 111.7, 110.8, 101.4, 88.7, 32.5, 31.7, 28.9, 28.85, 28.4, 26.3, 22.6, 15.4, 14.1, 11.0。

[0190] 1H NMR data of compound 3aa: 11H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 1H), 8.0 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.63 (q, J = 8.0 Hz, 2H), 7.54 (q, J = 6.0 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 6.60 (q, J = 6.8 Hz, 1H), 2.16 (t, J = 8.0 Hz, 2H), 1.90 (d, J = 7.6 Hz, 3H), 1.77 (s, 3H), 1.56 (s, 3H), 1.39 (p, J = 8.0 Hz, 2H), 1.07 - 0.99 (m, 10H), 0.82 (t, J = 7.2 Hz, 3H); 13 13C NMR (100 MHz, CDCl3) δ 190.8, 182.1, 168.0, 162.4, 152.1, 146.4, 144.4, 138.4, 137.6, 136.0, 134.5, 131.2, 129.08, 129.02, 128.5, 127.6, 125.3, 125.2, 125.1, 120.6, 111.4, 110.8, 101.2, 88.6, 32.5, 31.6, 28.8, 28.7, 28.2, 26.1, 22.5, 15.5, 14.0, 10.5。

[0191] 25. The synthesis process of compounds 3ab and 3ac includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound ab (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, and perform chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate). The resulting mixture is concentrated under reduced pressure. Using petroleum ether and ethyl acetate as eluents, silica gel column chromatography is used to purify to obtain compounds 3ab and 3ac. The yield of 3ab is 36%, and the yield of 3ac is 36%. The reaction route is as follows:

[0192]

[0193] 1H NMR data of compound 3ab: 11H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 6.74 - 6.69 (m, 4H), 6.60 (q, J = 6.4 Hz, 1H), 6.49 (s, 1H), 4.90 (dd, J = 11.6, 3.6 Hz, 1H), 3.49 (dd, J = 14.8, 3.6 Hz, 1H), 3.16 - 3.09 (m, 1H), 2.17 (t, J = 7.2 Hz, 2H), 1.87 (d, J = 10.8 Hz, 6H), 1.72 (s, 3H), 1.39 - 1.34 (m, 2H), 1.25 (s, 10H), 0.89 - 0.86 (m, 3H). 13 13C NMR (100 MHz, CDCl3) δ 191.2, 182.2, 168.6, 168.3, 164.4, 156.3, 151.5, 146.8, 144.6, 137.8, 129.6, 125.1, 124.9, 116.3, 112.1, 111.6, 100.7, 88.7, 53.8, 36.8, 32.6, 31.7, 29.03, 29.02, 28.99, 27.8, 26.2, 22.6, 15.4, 14.1, 10.8。

[0194] NMR data of compound 3ac: 1 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 6.90 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.0 Hz, 2H), 6.57 (q, J = 6.8 Hz, 1H), 6.49 (s, 1H), 4.98 - 4.86 (m, 1H), 3.84 (s, 3H), 3.50 (d, J = 10.0 Hz, 1H), 3.34 - 3.16 (m, 1H), 2.22 (t, J = 7.2 Hz, 2H), 1.89 (d, J = 6.8 Hz, 3H), 1.86 (s, 3H), 1.65 (s, 3H), 1.44 - 1.39 (m, 2H), 1.37 - 1.34 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 190.6, 181.9, 168.3, 168.0, 163.3, 156.5, 151.5, 146.9, 144.5, 137.5, 130.0, 125.0, 124.7, 116.3, 112.2, 111.5, 100.6, 99.9, 88.4, 53.6, 38.0, 32.6, 31.7, 29.7, 29.04, 28.99, 27.9, 26.2, 22.6, 15.5, 14.1, 10.7。

[0195] 26. The synthesis process of compounds 3ad and 3ae includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound ad (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform column chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compounds 3ad and 3ae. The yield of 3ad is 35%, and the yield of 3ae is 35%. The reaction route is as follows:

[0196]

[0197] 1H NMR data of compound 3ad: 1 H NMR(500MHz,CDCl3)δ8.02(s,1H),6.64(s,1H),6.54(q,J=8.0Hz,1H),5.14(q,J=5.0Hz,1H),3.86(s,3H),2.68 - 2.57(m,3H),2.56 - 2.50(m,1H),2.41 - 2.32(m,1H),2.25 - 2.16(m,1H),2.10(s,3H),1.87(d,J=8.0Hz,3H),1.81(s,3H),1.72(s,3H),1.70 - 1.63(m,2H),1.43(p,J=7.0Hz,2H),1.37 - 1.27(m,8H),0.90 - 0.87(m,3H). 13 C NMR(100MHz,CDCl3)δ191.0,182.2,168.7,168.1,163.1,150.8,146.7,143.6,137.5,125.1,112.3,111.4,101.4,88.5,53.5,32.8,31.7,31.1,30.0,29.15,29.09,29.0,28.1,26.2,22.6,15.4,15.3,14.0,10.7。

[0198] 1H NMR data of compound 3ae: 11H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 6.63 (s, 1H), 6.56 (q, J = 6.8 Hz, 1H), 5.18 - 5.07 (m, 1H), 3.78 (s, 3H), 2.74 - 2.54 (m, 4H), 2.51 - 2.42 (m, 1H), 2.33 - 2.20 (m, 1H), 2.14 (s, 3H), 1.88 (d, J = 6.8 Hz, 3H), 1.84 (s, 3H), 1.69 (s, 3H), 1.66 - 1.57 (m, 4H), 1.46 - 1.27 (m, 10H), 0.88 (t, J = 6.0 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 191.0, 182.2, 168.7, 168.1, 163.1, 150.9, 146.7, 143.6, 137.5, 125.1, 112.3, 111.4, 101.4, 88.5, 53.5, 32.8, 31.7, 31.1, 30.0, 29.14, 29.08, 29.0, 28.1, 26.2, 22.6, 15.4, 15.3, 14.0, 10.7。

[0199] 27. The synthesis process of compounds 3af and 3ag includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound af (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the obtained mixture under reduced pressure. Purify by silica gel column chromatography with petroleum ether and ethyl acetate as the eluent to obtain compounds 3af and 3ag. The yield of 3af is 37%, and the yield of 3ag is 37%. The reaction route is as follows:

[0200]

[0201] 1H NMR data of compound 3af: 11H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 6.64 (s, 1H), 6.54 (qd, J = 6.8, 0.8 Hz, 1H), 4.57 (dd, J = 10.0, 5.2 Hz, 2H), 3.13 - 3.03 (m, 2H), 2.53 - 2.49 (m, 2H), 2.27 - 2.18 (m, 1H), 2.10 - 2.00 (m, 1H), 1.87 (dd, J = 7.2, 0.8 Hz, 3H), 1.814 - 1.809 (m, 3H), 1.71 (s, 3H), 1.61 - 1.51 (m, 4H), 1.49 (s, 9H), 1.40 (s, 11H), 1.34 - 1.26 (m, 10H), 0.90 - 0.86 (m, 3H). 13 13C NMR (100 MHz, CDCl3) δ 190.9, 182.1, 168.3, 167.7, 165.0, 155.9, 150.6, 146.1, 144.0, 137.3, 135.5, 124.6, 111.8, 100.8, 88.7, 84.5, 32.9, 31.7, 30.4, 29.5, 29.2, 29.1, 29.0, 28.3, 28.3, 27.9, 26.1, 23.1, 22.6, 15.3, 14.0, 10.9。

[0202] 1H NMR data of compound 3ag: 1 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 6.63 (s, 1H), 6.54 (qd, J = 6.8, 1.2 Hz, 1H), 4.64 (s, 1H), 4.55 (dd, J = 8.8, 6.4 Hz, 1H), 3.14 (q, J = 6.8 Hz, 2H), 2.54 - 2.51 (m, 2H), 2.32 - 2.23 (m, 1H), 2.02 - 1.94 (m, 1H), 1.86 - 1.84 (m, 3H), 1.83 - 1.82 (m, 3H), 1.74 (s, 1H), 1.70 (s, 3H), 1.58 (p, J = 7.2 Hz, 4H), 1.405 (s, 11H), 1.413 (s, 9H), 1.36 - 1.25 (m, 10H), 0.89 - 0.86 (m, 3H). 1313C NMR (100 MHz, CDCl3) δ 191.1, 182.1, 168.2, 167.2, 163.0, 156.0, 150.6, 146.4, 143.7, 137.7, 124.9, 112.0, 111.6, 100.9, 88.5, 84.3, 32.9, 31.7, 31.6, 29.7, 29.2, 29.1, 29.0, 28.3, 28.2, 27.7, 26.5, 23.3, 22.5, 15.3, 14.0, 10.6.

[0203] 28. The synthesis process of compounds 3ah and 3ai includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound af (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, and perform column chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate). The resulting mixture is concentrated under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compounds 3ah and 3ai. The yield of 3ah is 32%, and the yield of 3ai is 33%. The reaction route is as follows:

[0204]

[0205] 1H NMR data of compound 3ah: 1 1H NMR (500 MHz, CDCl3) δ 8.81 (s, 1H), 8.28 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.65 (s, 1H), 6.61 (q, J = 6.0 Hz, 1H), 6.41 (s, 1H), 5.09 (dd, J = 11.0, 4.0 Hz, 1H), 3.93 (s, 3H), 3.74 (dd, J = 5.0, 15.0, 1H), 3.39 (dd, J = 15.0, 11.0 Hz, 1H), 2.09 - 2.02 (m, 2H), 1.89 - 1.83 (m, 6H), 1.72 (s, 3H), 1.30 - 1.06 (m, 10H),

[0206] 1.04 - 0.96 (m, 2H), 0.88 (t, J = 7.0 Hz, 3H). 1313C NMR (100 MHz, CDCl3) δ 191.2, 182.2, 169.1, 168.4, 164.9, 146.4, 137.9, 136.4, 136.0, 126.2, 124.8, 123.6, 122.8, 122.5, 120.2, 117.2, 112.2, 112.1, 111.4, 88.9, 53.8, 32.4, 31.8, 29.1, 29.0, 28.9, 28.2, 27.8, 26.3, 22.7, 15.5, 14.2, 11.0。

[0207] 1H NMR data of compound 3ai: 1 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.01 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.99 (s, 1H), 6.56 (q, J = 5.6 Hz, 1H), 6.42 (s, 1H), 5.09 (dd, J = 9.6, 4.8 Hz, 1H), 3.87 (s, 3H), 3.79 (dd, J = 15.2, 4.0 Hz, 1H), 3.48 (dd, J = 15.2, 10.4 Hz, 1H), 2.11 (t, J = 8.8 Hz, 2H), 1.92 - 1.84 (m, 6H), 1.53 (s, 3H), 1.31 - 1.16 (m, 10H), 1.13 - 1.10 (m, 2H), 0.88 (t, J = 6.8 Hz, 3H). 13 13C NMR (100 MHz, CDCl3) δ 190.8, 182.0, 168.5, 168.3, 163.4, 146.6, 137.7, 136.4, 136.3, 126.6, 125.0, 124.0, 122.7, 120.2, 117.2, 112.3, 112.1, 111.3, 107.3, 100.6, 88.5, 53.6, 32.5, 31.8, 29.8, 29.1, 29.04, 28.96, 27.9, 26.3, 22.7, 15.5, 14.2, 10.8。

[0208] 29. The synthesis process of compounds 3aj and 3ak includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound aj (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, and perform chromatographic analysis of the residue on silica gel (eluted with petroleum ether / ethyl acetate). The resulting mixture is concentrated under reduced pressure. Using petroleum ether and ethyl acetate as eluents, silica gel column chromatography is used to purify to obtain compounds 3aj and 3ak. The yield of 3aj is 36%, and the yield of 3ak is 36%. The reaction route is as follows:

[0209]

[0210] 1H NMR data of compound 3aj: 1 H NMR(400MHz,CDCl3)δ8.15(s,1H),6.67(s,1H),6.65 - 6.60(m,1H),4.70 - 4.61(m,2H),3.87(s,3H),3.36(s,1H),2.53(t,J=8.0Hz,2H),1.88(d,J=7.2Hz,3H),1.81(s,3H),1.72(s,3H),1.64 - 1.55(m,2H),1.44 - 1.24(m,13H),0.89 - 0.85(m,3H). 13 C NMR(100MHz,CDCl3)δ191.2,182.1,168.2,167.8,163.7,150.8,146.8,144.2,138.0,137.4,124.1,111.8,111.1,100.8,88.6,67.7,66.0,53.6,33.0,31.7,29.10,29.08,28.99,28.0,26.4,22.6,19.7,15.5,14.0,10.7。

[0211] 1H NMR data of compound 3ak: 1 H NMR(400MHz,CDCl3)δ8.15(s,1H),6.67(s,1H),6.62 - 6.53(m,1H),4.71 - 4.64(m,2H),3.81(s,3H),2.57(t,J=8.0,2H),1.88(d,J=7.6Hz,3H),1.84(s,3H),1.67(s,3H),1.61(p,J=8.0Hz,2H),1.40(p,J=7.2Hz,2H),1.36 - 1.25(m,11H),0.90 - 0.84(m,3H). 1313C NMR (100 MHz, CDCl3) δ 190.7, 182.1, 168.3, 167.4, 162.6, 151.3, 146.6, 144.4, 137.9, 137.5, 124.6, 111.6, 111.4, 100.6, 67.5, 66.3, 53.4, 33.1, 31.7, 29.1, 29.0, 28.0, 26.4, 22.6, 20.1, 15.4, 14.0, 10.6。

[0212] 30. The synthesis process of compound 3al includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound al (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform column chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography with petroleum ether and ethyl acetate as the eluent to obtain compound 3al with a yield of 65%. The reaction route is as follows:

[0213]

[0214] 1H NMR data of compound 3al: 1 1H NMR (400 MHz, CDCl 3, two inseparable diastereomers) δ 8.22 (s, 0.41H), 8.00 (s, 0.49H), 7.30 - 7.29 (m, 2H), 7.23 - 7.16 (m, 1H), 7.11 - 7.09 (m, 1H), 6.95 - 6.93 (m, 1H), 6.64 (q, J = 6.8 Hz, 0.42H), 6.57 (q, J = 6.8 Hz, 0.49H), 6.44 (s, 1H), 4.93 - 4.89 (m, 1H), 3.90 (s, 1.40H), 3.83 (s, 1.45H), 3.63 - 3.53 (m, 1H), 3.31 - 3.23 (m, 1H), 2.21 - 2.08 (m, 2H), 1.95 - 1.88 (m, 6H), 1.72 (s, 1.41H), 1.71 (s, 1.55H), 1.43 - 1.25 (m, 12H), 0.88 (t, J = 6.4 Hz, 3H); 1313C NMR (100 MHz, CDCl3, two inseparable diastereomers) δ 191.4, 190.8, 182.2, 182.0, 168.5, 168.2, 168.0, 164.3, 163.2, 150.54, 150.49, 146.6, 143.7, 143.6, 137.7, 137.5, 135.7, 135.3, 134.3, 134.2, 129.2, 129.1, 128.9, 128.7, 128.1, 128.0, 125.1, 125.0, 112.1, 111.9, 111.2, 111.0, 101.2, 88.7, 88.4, 53.8, 53.5, 38.7, 37.2, 32.5, 32.4, 31.7, 29.7, 29.01, 28.97, 27.8, 27.7, 26.1, 26.0, 22.6, 15.42, 15.41, 14.0, 10.9, 10.7。

[0215] 31. The synthesis process of compound 3am includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound am (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, and perform column chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate). The resulting mixture is concentrated under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3am with a yield of 75%. The reaction route is as follows:

[0216]

[0217] 1H NMR data of compound 3am: 11H NMR (400 MHz, CDCl3, two inseparable diastereomers) δ 8.08 (s, 0.44H), 8.08 (s, 0.45H), 6.62 (s, 1H), 6.58 - 6.52 (m, 1H), 4.25 (t, J = 10.4 Hz, 1H), 3.84 (s, 1.54H), 2.63 - 2.43 (m, 3H), 1.87 (s, 3H), 1.83 (d, J = 18.0 Hz, 3H), 1.69 (s, 1.37H), 1.68 (s, 1.42H), 1.66 - 1.59 (m, 2H), 1.42 (p, J = 7.2 Hz, 2H), 1.35 - 1.27 (m, 8H), 1.12 (d, J = 4.4 Hz, 1.41H), 1.11 (d, J = 4.0 Hz, 1.54H), 0.94 (d, J = 6.4 Hz, 1.57H), 0.89 - 0.85 (m, 3H), 0.70 (d, J = 6.4 Hz, 1.48H). 13 13C NMR (100 MHz, CDCl 3, two inseparable diastereomers) δ 190.8, 182.2, 182.1, 168.9, 168.3, 168.1, 163.6, 162.6, 150.7, 150.5, 146.5, 146.4, 143.6, 143.5, 137.7, 135.5, 135.1, 135.0, 125.0, 112.2, 112.0, 111.6, 111.5, 101.1, 101.0, 88.6, 88.4, 67.2, 67.1, 53.3, 53.0, 32.9, 32.8, 31.69, 31.66, 30.5, 29.09, 29.06, 29.0, 28.2, 28.1, 26.2, 25.9, 22.5, 19.40, 19.38, 18.8, 18.4, 15.4, 14.0, 10.6。

[0218] 32. The synthesis process of compound 3an includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound an (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform column chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography with petroleum ether and ethyl acetate as the eluent to obtain compound 3an with a yield of 75%. The reaction route is as follows:

[0219]

[0220] NMR data of compound 3an: 1 H NMR(400MHz,CDCl 3, two inseparable diastereomers)δ8.21(s,0.45H),8.06(s,0.43H),6.62(s,1H),6.57-6.50(m,1H),4.50(d,J=14.4Hz,0.45H),4.31(d,J=10.8Hz,0.48H),3.84(s,1.56H),3.76(s,1.41H),2.55(t,J=7.6Hz,2H),2.30-2.18(m,1H),1.87(s,3H),1.83(d,J=14.0Hz,3H),1.68(s,3H),1.66-1.58(m,2H),1.44-1.37(m,2H),1.36-1.29(m,8H),1.08-1.05(m,3H),0.94(t,J=7.2Hz,2H),0.88-0.82(m,6H). 13 C NMR(100MHz,CDCl 3, two inseparablediastereomers)δ190.8,190.6,182.2,182.1,169.0,168.4,168.2,168.1,164.1,162.6,150.7,150.6,146.4,146.1,143.7,143.5,137.7,137.4,135.3,135.1,125.0,124.9,112.08,112.06,111.6,111.5,101.1,100.9,88.6,88.4,66.2,53.2,53.0,37.6,36.6,32.9,32.8,31.6,29.09,29.06,29.04,28.9,28.1,28.0,26.1,26.0,25.0,24.8,15.6,15.5,15.35,15.29,14.0,10.9,10.74,10.7,10.6。

[0221] 33. The synthesis process of compound 3ao includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound ao (1.0 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, and perform chromatographic analysis of the residue on silica gel (eluted with petroleum ether / ethyl acetate). The resulting mixture is concentrated under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3ao with a yield of 73%. The reaction route is as follows:

[0222]

[0223] NMR data of compound 3an: 1 H NMR(400MHz,CDCl 3, two inseparable diastereomers)δ8.09(s,0.43H),7.93(s,0.51H),6.64(s,0.45H),6.62(s,0.50H),6.58 - 6.51(m,1H),4.80 - 4.72(m,1H),3.83(s,1.40H),3.76(s,1.56H),2.56 - 2.51(m,2H),2.21 - 1.96(m,2H),1.88 - 1.81(m,7H),1.70(s,1.44H),1.68(s,1.57H),1.67 - 1.56(m,2H),1.41(p,J=6.8Hz,2H),1.36 - 1.27(m,8H),1.01(dd,J=6.8,1.2Hz,3H),0.93(dd,J=6.8,2.4Hz,3H),0.87(t,J=6.8Hz,3H). 13 C NMR(100MHz,CDCl 3,two inseparable diastereomers) δ 190.9, 190.8, 182.3, 182.1, 169.6, 168.9, 168.2, 168.1, 164.4, 162.9, 150.3, 146.5, 146.2, 143.9, 143.6, 137.6, 137.4, 135.5, 125.1, 124.8, 111.9, 111.7, 111.6, 101.1, 101.0, 99.9, 88.6, 88.5, 59.6, 53.5, 53.3, 41.3, 39.4, 32.8, 32.7, 31.7, 29.2, 29.13, 29.09, 29.08, 29.0, 28.2, 28.0, 26.14, 26.07, 25.1, 24.5, 22.54, 22.47, 22.31, 22.29, 21.5, 15.4, 15.3, 14.0, 10.7, 10.6。

[0224] 34. The synthesis process of compound 3ap includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound 2g (2.2 mol) are added to a solution of compound ap (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 10 min, concentrate under vacuum, perform chromatographic analysis of the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the obtained mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as the eluent to obtain compound 3ap with a yield of 52%. The reaction route is as follows:

[0225]

[0226] 1H NMR data of compound 3ap: 1 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 2H), 6.64 (s, 2H), 6.55 (q, J = 7.2 Hz, 2H), 4.10 - 3.87 (m, 4H), 2.68 - 2.52 (m, 4H), 2.01 - 1.89 (m, 4H), 1.86 (d, J = 7.2 Hz, 6H), 1.80 (s, 6H), 1.71 - 1.61 (m, 10H), 1.47 - 1.27 (m, 20H), 0.86 (t, J = 6.8 Hz, 6H). 1313C NMR (126 MHz, CDCl3) δ 190.9, 181.5, 168.2, 164.5, 150.7, 146.3, 144.5, 138.2, 137.3, 124.5, 112.2, 111.9, 100.1, 88.6, 52.2, 32.2, 31.7, 29.29, 29.26, 29.1, 28.6, 27.5, 26.3, 22.6, 15.4, 14.0, 11.0.

[0227] 35. The synthesis process of compound 3aq includes: The reaction route is as follows. In a dry reaction eggplant-shaped flask, acetic acid (3.6 mol) and compound aq (1.2 mol) are added to a solution of compound 2g (1.0 mol) in tetrahydrofuran (3 L). Stir at room temperature for 3 d, concentrate under vacuum, perform chromatography on the residue on silica gel (eluted with petroleum ether / ethyl acetate), and concentrate the resulting mixture under reduced pressure. Purify by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain compound 3aq with a yield of 54%. The reaction route is as follows:

[0228]

[0229] 1H NMR data of compound 3ap: 1 1H NMR (400 MHz, Methanol-d4) δ 7.96 (s, 1H), 6.90 (s, 1H), 6.64 (q, J = 6.0 Hz, 1H), 4.55 - 4.44 (m, 1H), 4.35 - 4.26 (m, 1H), 4.25 - 4.20 (m, 2H), 3.86 - 3.75 (m, 2H), 3.68 - 3.52 (m, 4H), 3.47 (t, J = 5.6 Hz, 2H), 3.20 (s, 1H), 3.03 - 2.65 (m, 4H), 2.19 (t, J = 7.6 Hz, 2H), 1.95 (s, 4H), 1.92 - 1.86 (m, 5H), 1.79 - 1.51 (m, 9H), 1.51 - 1.30 (m, 13H), 0.92 - 0.87 (m, 3H). 1313C NMR (125 MHz, Methanol-d4) δ 190.1, 180.4, 174.0, 167.9, 162.7, 153.5, 146.1, 145.7, 139.0, 137.1, 123.7, 111.5, 111.3, 97.3, 88.0, 69.8, 69.3, 68.6, 61.4, 59.6, 55.0, 52.4, 39.1, 38.3, 34.7, 31.3, 31.0, 28.4, 28.3, 28.2, 27.8, 27.5, 27.4, 24.8, 24.6, 21.7, 13.5, 12.5, 8.9。

[0230] In terms of applicability, differently substituted compounds can efficiently form angular rings. The substituents can be either aliphatic chains, aromatic rings, or heterocyclic compounds. The yield of the reaction with primary amines does not change significantly with the variation of the linking group.

[0231] Application / Performance Testing

[0232] Taking the compounds synthesized in Example 5 above as an example, the anti-tumor activity performance of these eight compounds in activating immune cells was detected. Specifically as follows:

[0233] NK-92 cells in the logarithmic growth phase were counted and then seeded on a cell culture plate. Subsequently, IL-15, solvent, and compounds at different concentrations were added. The final concentration of the compounds was 1 μM, and they were cultured in an incubator for 72 h. The NK-92 cells were centrifuged to remove the drugs contained in the supernatant, resuspended with fresh medium, and the NK-92 cells in each group and target cells (Hepg2 cells) were added to a 96-well plate at an effector-to-target ratio of 5:1. After centrifugation to allow the effector cells and target cells to fully contact at the bottom of the plate, they were cultured for 5 h. Detection was performed using an LDH kit and the tumor killing percentage was calculated. The results are as Figure 1 shown, Figure 1 It is a statistical chart of the anti-tumor activity of NK cells under the culture of the compounds prepared in Example 5.

[0234] Figure 1The results showed that all eight compounds prepared in Example 5 had the activity of activating NK cells against tumors; Compound 3u (i.e., WDYSK-4-28-1 in the figure) showed the activity of activating NK cells against tumors, and the difference was statistically significant, and the activity was equivalent to that of IL-5; both Compound 3v (i.e., WDYSK-4-28-2 in the figure) and Compound 3m (i.e., WDYSK-4-30 in the figure) showed relatively high activities of activating NK cells against tumors; Compound 3o (i.e., WDYSK-4-31 in the figure), 3aj (i.e., WDYSK-4-33-1 in the figure), 3ak (i.e., WDYSK-4-33-2 in the figure), 3c (i.e., WDYSK-4-42 in the figure) and 3b (i.e., WDYSK-4-46 in the figure) showed relatively low activities of activating NK cells against tumors.

[0235] The above examples only illustrate several embodiments of the present invention and should not be construed as limiting the scope of the present invention. It should be noted that for other persons skilled in the art, modifications, substitutions, improvements, etc. can be made without departing from the concept and scope of the present invention, and these all belong to the protection scope of the present invention. Therefore, the patent protection scope of the present invention should be subject to the claims described.

Claims

1. An Azaphilone compound, characterized in that, The general structural formula of the Azaphilone compound is shown in formula (I); In formula (I), the R 1 is hydrogen, fluorine, chlorine, bromine or iodine; the R 2 is methyl, ethyl, cis-2-butenyl, phenyl, furyl or thienyl.

2. The Azaphilone compound according to claim 1, characterized in that, The structural formula of the Azaphilone compound is any one of the following:

3. A method for preparing the Azaphilone compound according to claim 1 or 2, characterized in that, The preparation method adopts the following steps: under an oxygen-free condition, add the compound shown in formula (III) to the organic solvent solution of the compound shown in formula (II), stir, add a catalyst, heat for reaction to obtain the Azaphilone compound shown in formula (I); the reaction route is shown in Route 1: Route 1.

4. The preparation method according to claim 3, characterized in that, The molar volume ratio of the compound shown in formula (II), the compound shown in formula (III), the catalyst and the organic solvent is 1.00 mol: 1.50 mol: 2.00 mol: 3.00 L; The stirring adopts the following steps: first stir at room temperature for 10 min, and then stir at 110 °C for 1 h; The heating reaction is carried out under stirring, the temperature is 110 °C, and the time is 1 h; The organic solvent is toluene, tetrahydrofuran, carbon tetrachloride or dichloroethane; The catalyst is triethylamine or diisopropylethylamine; After the reaction is completed, the reaction solution needs to be quenched with 1M HCl, the obtained solution is extracted three times with ethyl acetate, dried with anhydrous sodium sulfate, then concentrated in vacuo and concentrated under reduced pressure, and silica gel column chromatography is carried out using petroleum ether and ethyl acetate as eluents to purify to obtain the Azaphilone compound.

5. A derivative of the Azaphilone compound according to claim 1 or 2, characterized in that, The general structural formula of the derivative is shown in formula (IV); In formula (IV), the R 1 is hydrogen, fluorine, chlorine, bromine or iodine; the R 2 is methyl, ethyl, cis-2-butenyl, phenyl, furyl or thienyl; the R 3 is benzyl, naphthyl or an aliphatic chain group.

6. The derivative according to claim 5, characterized in that, The structural formula of the derivative is any one of the following:

7. A method for preparing the derivative according to claim 5 or 6, characterized in that, The preparation method adopts the following steps: add acetic acid and the compound shown in formula (V) to the organic solvent solution of the compound shown in formula (I), stir, and react to obtain the derivative shown in formula (IV); the reaction route is shown in Route 2: Route 2.

8. The preparation method according to claim 7, characterized in that, The molar volume ratio of the compound shown in formula (I), the compound shown in formula (V), acetic acid and the organic solvent is 1.00 mol: 1.20 mol: 3.60 mol: 3.00 L; The organic solvent is toluene, tetrahydrofuran, carbon tetrachloride or dichloroethane; The stirring time is 10 min; The reaction is carried out at room temperature; After the reaction is completed, the reaction solution needs to be concentrated in vacuo and concentrated under reduced pressure, and silica gel column chromatography is carried out using petroleum ether and ethyl acetate as eluents to purify to obtain the derivative.

9. The preparation method according to claim 3, characterized in that, The preparation method of the compound shown in formula (II) adopts the following steps: (1). Add copper iodide and bis(triphenylphosphine)palladium dichloride to the dimethylformamide solution of the compound shown in formula (VI), then add compound A and triethylamine. The molar volume ratio of the compound shown in formula (VI), copper iodide, bis(triphenylphosphine)palladium dichloride, compound A, triethylamine and dimethylformamide is 1.00 mol: 0.10 mol: 0.10 mol: 1.50 mol: 3.28 mol: 5.00 L, react at 60 °C for 16 h to obtain the compound shown in formula (VII); compound A is decyne; the reaction route is shown in Route 3: Route 3; (2) Add silver nitrate, trifluoroacetic acid to the dichloromethane solution of the compound shown in formula (VII), stir at room temperature for 30 min, then add 2-iodoxybenzoic acid and tetrabutylammonium bromide. The molar volume ratio of the compound shown in formula (VII), silver nitrate, 2-iodoxybenzoic acid, tetrabutylammonium bromide, dichloromethane, and trifluoroacetic acid is 1.00 mol : 0.01 mol : 1.10 mol : 0.01 mol : 1.00 L : 0.10 L, and react at room temperature for 4 h to obtain the compound shown in formula (VIII); (3) Add N-chlorosuccinimide to the acetonitrile solution of the compound shown in formula (VIII) obtained in step (2), and react at room temperature for 24 h to obtain the compound shown in formula (IX); The molar volume ratio of the compound shown in formula (VIII), N-chlorosuccinimide, and acetonitrile is 1.00 mol : 1.20 mol : 2.00 L; Alternatively, add N-bromosuccinimide to the acetonitrile solution of the compound shown in formula (VIII) obtained in step (2), and react at room temperature for 6 h to obtain the compound shown in formula (X); The molar volume ratio of the compound shown in formula (VIII), N-bromosuccinimide, and acetonitrile is 1.00 mol : 1.20 mol : 2.00 L; Alternatively, add N-iodosuccinimide to the acetonitrile solution of the compound shown in formula (VIII) obtained in step (2), and react at room temperature for 3 h to obtain the compound shown in formula (XI); The molar volume ratio of the compound shown in formula (VIII), N-iodosuccinimide, and acetonitrile is 1.00 mol : 1.20 mol : 2.00 L; The compound shown in formula (II) includes the compound shown in formula (VIII), the compound shown in formula (IX), the compound shown in formula (X), and the compound shown in formula (XI).

10. Use of the Azaphilone compound according to claim 1 and / or the derivative of the Azaphilone compound according to claim 5, characterized in that, The Azaphilone compounds can be used to prepare anti-tumor drugs; The derivatives of the Azaphilone compounds can be used to prepare anti-tumor drugs.

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