Improved SF5Cl synthesis method, synthesis method for preparing beta-SF5-ketone compound by using SF5Cl synthesis method and application of beta-SF5-ketone compound

Abstract

The invention discloses an improved SF5Cl synthesis method, a synthesis method for preparing beta-SF5-ketone compounds by using the SF5Cl and application of the beta-SF5-ketone compounds, and belongs to the technical field of medicinal chemistry. In the structural formula, R1 group is alkyl, olefin, heteroarene or aryl, and R2 group is selected from alkyl. The preparation method comprises the following steps: adding beta, gamma-unsaturated ketone and a high-concentration pentafluorothionyl chloride normal hexane solution into a solvent together, and then carrying out free radical 1, 2 carbonyl migration in beta, gamma-unsaturated ketone molecules under a light induction condition to prepare the beta-SF5-ketone compound. According to the method, the high-concentration pentafluorosulfur chlorine n-hexane solution is prepared in a distillation mode, the yield is up to 67%, and the pentafluorosulfur chlorine n-hexane solution is used for preparing various valuable beta-SF5-ketone compounds. The conversion has wide functional group tolerance and can be efficiently used for later modification of complex molecules, the highest yield reaches 77%, chemical and regioselectivity is excellent and far better than that of a traditional method, and the problem that the traditional method is hindered to a specific functional group reaction or poor in selectivity can be solved.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and in particular relates to an improved SF5Cl synthesis method and a synthesis method and application thereof for preparing β-SF5-ketone compounds. Background Art

[0002] Fluorine has been widely used in the field of drug design and development. Introducing fluorine atoms into compounds can significantly change their lipophilicity and dissociation constant (pK a ) and metabolic stability. Common methods for introducing fluorine atoms into compounds include direct fluorination or the addition of fluorinated functional groups. The most common example of the latter method is the trifluoromethyl group; however, in the field of medicinal chemistry, the exploration of more fluorinated functional groups never stops.

[0003] Pentafluorosulfenyl (SF5), a relatively new class of fluorinated building blocks, is gaining increasing attention in medicinal chemistry. Its unique properties, such as high electronegativity and significant lipophilicity, offer novel possibilities for drug design, such as the ability to effectively modulate a drug molecule's electron cloud distribution, lipophilicity, and interaction patterns with biological targets, demonstrating its potential applications.

[0004] At present, pentafluorosulfonyl has shown potential application value in some existing drug molecule studies. For example, in the study of triazolopyrimidine compound DSM-265, it became the first pentafluorosulfonyl drug molecule to enter clinical research. Biochemical and cell analysis showed that its prototype small molecule DSM12 had weak activity; when the para position of the benzene ring was replaced by a methyl group, DSM97 had moderate inhibitory activity; replacing the methyl group with a trifluoromethyl group increased the activity of DSM74 by 15 times; further introducing an ethyl group on the triazole ring, the activity of DSM280 increased by another 3-5 times; replacing the CH2 in the ethyl group with CF2, the IC of DSM267 50 The value can reach 38nM, and the cell EC 50 The value can reach 10nM. In vitro testing of its pentafluorosulfonyl analogue, DSM265, showed comparable activity to DSM267. Furthermore, in animal model studies, DSM265 demonstrated superior drugability and is currently undergoing Phase II clinical trials in the United States. This case demonstrates the potential of pentafluorosulfonyl in optimizing drug activity and properties.

[0005] Furthermore, a structure-activity relationship study of rimonabant revealed that its pentafluorosulfanyl analog, while not as active as rimonabant (six times less), was 10 times more potent than its trifluoromethyl analog, still possessing advantages in certain biological properties and worthy of further study. This further demonstrates that pentafluorosulfanyl can produce unique effects in drug molecule modification, providing a new direction for drug development. With the advancement of synthetic methodology, an increasing number of pentafluorosulfanyl compounds have been successfully synthesized, and the commercial availability of pentafluorosulfanyl building blocks has also increased significantly, which, to a certain extent, has helped accelerate the application of pentafluorosulfanyl as a pharmacophore in medicinal chemistry.

[0006] Despite the potential of pentafluorosulfonyl compounds in drug development, their development faces numerous limitations. A comprehensive review and analysis of the existing literature reveals that nearly all research on bioactive molecules is limited to substituted aromatic ring systems, with limited expansion to other structural types. This limitation has resulted in a significant gap in the research of aliphatic pentafluorosulfonated drug molecules.

[0007] Furthermore, the current lack of truly stable and convenient pentafluorosulfenylation reagents often results in harsh reaction conditions and high requirements for reaction equipment, which also limits the large-scale preparation and application of pentafluorosulfenyl compounds. Furthermore, the lack of a gentle and efficient methodology for introducing pentafluorosulfenyl groups makes it difficult to flexibly and efficiently incorporate pentafluorosulfenyl groups into molecules of various structures during drug molecule design, hindering in-depth research and development of the potential role of pentafluorosulfenyl groups in a wider range of drug molecules.

[0008] The preparation of pentafluorosulfur chlorine (SF5Cl) encompasses a variety of methods. Traditional methods include reacting sulfur powder with chlorine trifluoride gas at temperatures not exceeding 105°C for four hours; reacting disulfur dichloride with fluorine gas at -80°C to 20°C for five hours, though the yield is only 13%; reacting sulfur tetrafluoride, chlorine gas, and cesium fluoride at 100°C to 150°C for six hours, achieving a 75% yield; and reacting sulfur tetrafluoride, chlorine gas, and nitrosyl fluoride at room temperature for 16 hours. These traditional methods have significant drawbacks. Firstly, the use of highly toxic gases such as sulfur tetrafluoride and chlorine fluoride as raw materials poses significant safety risks. Secondly, the reaction conditions often require either high or low temperatures, or the reaction time is extremely long, and some reactions result in low yields.

[0009] At the level of improved methods, the team of Academician Qing Fengling uses elemental sulfur, potassium fluoride and trichloroisocyanuric acid as raw materials and acetonitrile as solvent. It can be prepared at room temperature, but the reaction process must be protected from light. The method of patent number WO 2009152385 A2 is to react sulfur powder, chlorine gas, liquid bromine and potassium fluoride at room temperature for 5-14 days, with a yield of 95%. Patent number WO 2019229103 A1 is to use sulfur powder, trichloroisocyanuric acid and potassium fluoride to react in acetonitrile solvent at room temperature for 14 hours under the catalysis of trifluoroacetic acid. In addition, in the presence of catalyst N-methylpyrrolidone, a sulfur source is reacted with trichloroisocyanuric acid, stirred at room temperature in acetonitrile solvent for 48 hours, and the yield can reach 34%. However, these improved methods also face difficulties, such as the generally long reaction time, unstable yield, some reactions require specific catalysts or conditions, and the product concentration is low.

[0010] In view of this, developing efficient and practical synthetic methods to construct functional pentafluorosulfur compounds is of vital importance to fill the current technological gaps and promote the development of medicinal chemistry. Summary of the Invention

[0011] To address the aforementioned deficiencies in the prior art, the present invention provides an improved SF5Cl synthesis method and its synthesis and use for preparing β-SF5-ketone compounds. This method purifies a high-concentration n-hexane solution of pentafluorosulfuryl chloride and uses it to prepare a variety of valuable β-SF5-ketone compounds. This transformation exhibits broad functional group tolerance and can be efficiently used for late-stage modification of complex molecules, achieving yields up to 77% and exhibiting excellent chemical and regioselectivity, far exceeding those of conventional methods. This method overcomes the problems of traditional methods with limited reactivity or poor selectivity for specific functional groups.

[0012] To achieve the above-mentioned purpose, the technical solution adopted by the present invention to solve the technical problem is:

[0013] The object of the present invention is to provide a β-SF5-ketone compound, the structural formula of which is as follows:

[0014]

[0015] Among them, R 1 The group is alkyl, alkene, heteroaromatic, aryl, aromatic, R 2 The group is an alkyl group.

[0016] Furthermore, R 1 The group is selected from various substituted alkyl, alkene, heteroaromatic, aryl or aromatic groups, such as halogen, alkane, cyano, alkoxy, ether, isobutyryl, trifluoromethyl, trifluoromethylthio, menthol, 2-camphenol, RU 58841, adamantanecarboxylic acid, ibuprofen, 7-hydroxycoumarin, 6-hydroxyflavone, dihydrocholesterol, epiandrosterone, testosterone or sisalogenin; R2 It is a methyl group.

[0017] Further, the β-SF5-ketone compound is:

[0018]

[0019]

[0020] Another object of the present invention is to provide a method for preparing the above-mentioned β-SF5-ketone compound, comprising the following steps:

[0021] (1) preparing a n-hexane solution of pentafluorosulfuryl chloride with a concentration greater than 0.4 M;

[0022] (2) Add β,γ-unsaturated ketone and pentafluorosulfuryl chloride n-hexane solution into a solvent, and then carry out 1,2-carbonyl migration of free radicals in the β,γ-unsaturated ketone molecule under light of 360-365nm at 32-35℃ to prepare β-SF5- / ketone compound. The reaction formula is as follows:

[0023]

[0024] Furthermore, the molar ratio of β,γ-unsaturated ketone to pentafluorosulfuryl chloride is 0.10:0.10-0.12.

[0025] Furthermore, the structural formula of β,γ-unsaturated ketone is as follows:

[0026]

[0027] Among them, R 1 The group is selected from various substituted alkyls, olefins, heteroaromatics, aryls or aromatics, such as halogen, alkane, cyano, alkoxy, ether, isobutyryl, trifluoromethyl, trifluoromethylthio, menthol, 2-camphenol, RU 58841, adamantanecarboxylic acid, ibuprofen, 7-hydroxycoumarin, 6-hydroxyflavone, dihydrocholesterol, epiandrosterone, testosterone or sisalogenin; the R2 group is an alkyl group.

[0028] Furthermore, the solvent used in step (2) is 1,2-dichloroethane with a concentration of 0.1M.

[0029] Furthermore, in step (2), the wavelength is 365 nm, the reaction temperature is 35° C., and the reaction time is 1 h.

[0030] Another object of the present invention is to use β-SF5-keto compounds for subsequent derivatization, including the following structural formula:

[0031]

[0032] Another object of the present invention is to provide an improved SF5Cl synthesis method, which comprises the following process:

[0033] Under the catalysis of trifluoroacetic acid, sulfur powder, trichloroisocyanuric acid and potassium fluoride are used as raw materials, reacted in a solvent at room temperature for 14 to 16 hours, and then distilled to obtain a hexane solution of pentafluorosulfuryl chloride with a concentration greater than 0.4M.

[0034] Another object of the present invention is to provide the use of the above-mentioned β-SF5-ketone compounds in the preparation of anti-tumor drugs.

[0035] Furthermore, the tumor is liver cancer, colon cancer, cervical cancer, prostate cancer, lung cancer, breast cancer or myeloma.

[0036] Another object of the present invention is to provide an anti-tumor drug, which comprises the above-mentioned β-SF5-ketone compound and a pharmaceutically acceptable adjuvant thereof.

[0037] Beneficial effects of the present invention:

[0038] The present invention optimizes the purification method for SF5Cl, successfully obtaining a high-concentration n-hexane solution of chlorinated pentafluorosulfur via distillation. Chlorinated pentafluorosulfur is gaseous under standard conditions. In practice, n-hexane is often used as a solvent to dissolve it for subsequent use. Previous studies have shown that the n-hexane solutions of chlorinated pentafluorosulfur prepared by these methods generally have relatively low concentrations. This limitation directly results in the need for large amounts of n-hexane as a solvent medium during the pentafluorosulfurization reaction to meet the required amount of chlorinated pentafluorosulfur. In stark contrast, the high-concentration n-hexane solution of chlorinated pentafluorosulfur prepared by the present invention significantly reduces the amount of n-hexane used while achieving the same reaction effect. When other solvents are used to construct the reaction system, the presence of large amounts of n-hexane can significantly interfere with the target reaction process due to factors such as dilution effects and competing reactions. The present invention effectively avoids these potential effects, providing a more ideal, pure, and efficient reaction raw material for the pentafluorosulfurization reaction, and is expected to promote further research and application in this field.

[0039] This invention prepares a high-concentration n-hexane solution of pentafluorosulfuryl chloride by distillation and uses it to prepare a variety of valuable β-SF5-ketone compounds. This transformation exhibits broad functional group tolerance and can be efficiently used for the late-stage modification of complex molecules, achieving yields up to 77% and excellent chemical and regioselectivity, far exceeding traditional methods. It also overcomes the problems of traditional methods with blocked reactions or poor selectivity for specific functional groups. Furthermore, the resulting β-SF5-ketone compounds can be converted into diverse structures, laying the foundation for the construction of functional pentafluorosulfur compounds and the research of aliphatic pentafluorosulfurized drug molecules, with broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 is the inhibition curve of compound 5 on PC cells;

[0041] Figure 2 The colony formation experiment was used to detect the inhibitory effect of compound 5 on the number and size of tumor colonies;

[0042] Figure 3 The scratch assay was used to detect the inhibitory effect of compound 5 on tumor cell invasion;

[0043] Figure 4 Flow cytometry was used to detect the apoptosis of tumor cells induced by compound 5;

[0044] Figure 5 Compound 5 induces ROS production in tumor cells;

[0045] Figure 6 Compound 5 caused gene expression changes in the sequencing results;

[0046] Figure 7 GO analysis of the effects of compound 5 on the structural and functional changes of tumor cells;

[0047] Figure 8 KEGG analysis was performed to analyze the correlation between compound 5 and tumor suppressor pathways. DETAILED DESCRIPTION

[0048] The specific embodiments of the present invention are described below to facilitate understanding of the present invention by those skilled in the art. However, it should be clear that the present invention is not limited to the scope of the specific embodiments. For those skilled in the art, as long as various changes are within the spirit and scope of the present invention as defined and determined by the appended claims, these changes are obvious, and all inventions and creations utilizing the concepts of the present invention are protected.

[0049] Example 1 Improved Synthesis Method of Pentafluorosulfuryl Chloride

[0050] Under nitrogen, a thick-walled pressure flask (500 mL) equipped with a magnetic rod and wrapped in aluminum foil was charged with TCCA (33.50 g, 144 mmol, 4.5 equiv), spray-dried potassium fluoride powder (16.70 g, 288 mmol, 9.0 equiv), and sulfur powder (1.02 g, 32 mmol, 1.0 equiv). MeCN (160 mL) was then added, and the mixture was sealed with a screw cap. Trifluoroacetic acid (73.50 μL, 0.96 mmol, 0.03 equiv) was then added, and the mixture was stirred vigorously at room temperature in the dark for 16 h. After quenching the reaction, the pressure flask was cooled to -78°C in a liquid nitrogen-acetone bath and held for 20 min. The stopcock was then opened and the reaction mixture was transferred to a single-necked round-bottom flask (500 mL) at low temperature. Distillation was performed at 50°C for 2-4 h, and the gaseous products in the reaction flask were distilled into a receiving flask, which was cooled in a liquid nitrogen-acetone bath. Finally, the distilled fraction was added to 40 mL of n-hexane to obtain a highly concentrated colorless to light yellow SF5Cl n-hexane solution, which was used without further purification. After returning to room temperature, 5 μL of trifluoromethoxybenzene was used as an internal standard. 19 Determination of solution concentration by F NMR: A 0.3 mL volume of anhydrous CDCl3 and a 0.2 mL aliquot of the SF5Cl stock solution were added to an oven-dried 3 mm NMR tube. 19 F NMR data were collected using a pulse angle of 90°, a relaxation delay of 30 s, and an O1P of 33 ppm. (For example: 32.0 mmol, 54 mL, 0.40 M, yield: 68%). The prepared SF5Cl n-hexane solution should be stored in a refrigerator at -30°C, protected from light, and is recommended for use within five days. (Note: All steps must be performed in a well-ventilated fume hood.) The reaction equation is as follows:

[0051]

[0052] SF5Cl: 19 F NMR (565MHz, CDCl3) δ125.94 (d, J = 149.9Hz), 63.72–62.37 (m).

[0053] Example 2 Synthesis of β-SF5-ketone compound 3a

[0054] In a glove box, a 20 mL vial equipped with a magnetic stir bar was charged with a β,γ-unsaturated ketone (104.54 mg, 0.6 mmol, 1.0 equiv) and 1,2-dichloroethane (DCE, 6.0 mL, 0.10 M). The vial was sealed and removed from the glove box. Subsequently, sulfur pentafluoride (SF5Cl) (1.8 mL, 0.72 mmol, 1.2 equiv, 0.40 M in n-hexane) was injected into the reaction mixture using a 1 mL syringe in three 10-min intervals while stirring under 30 W, 365 nm LED light. The reaction mixture was then stirred at 35°C under 365 nm LED light for 30 min. Upon completion of the reaction, the reaction mixture was quenched with water and extracted three times with 1,2-dichloromethane (DCM). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the desired pure product 3a.

[0055]

[0056] R f =0.50 (petroleum ether / ethyl acetate=20:1), white solid, yield 91%;

[0057] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ8.11(d,J=8.2Hz,2H),8.06(d,J=8.3Hz,2H),4.63(dt,J=13.0,8.8Hz, 2H),4.33–4.15(m,1H),3.62–3.46(m,1H),1.56(s,3H),1.52(s,3H),1.24(d,J=6.8Hz,6H). 13 C NMR (151MHz, CDCl3) δ203.8, 196.8, 140.4, 139.8, 129.0, 128.9, 71.5 (p, J = 14.3Hz), 69.3, 53.2, 36.1, 32.9, 28.7, 19.1. 19 F NMR (565MHz, CDCl3) δ84.81–83.23 (m, 1F), 67.48 (dt, J = 145.7, 6.7Hz, 4F).

[0058] Example 3

[0059] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3b.

[0060]

[0061] Rf =0.50 (petroleum ether / ethyl acetate=20:1), white solid, yield 57%;

[0062] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ7.92(d,J=7.8Hz,2H),7.31(d,J=7.8Hz,2H),4.63(s,2H),4.38–4.14(m,1H),2.44(s,3H),1.54(s,3H),1.52(s,3H). 13 C NMR (151MHz, CDCl3) δ196.7,145.2,134.6,129.8,129.0,72.0–71.5(m),70.0,52.8,33.5,28.3,21.8. 19 FNMR (565MHz, CDCl3) δ85.03–83.51 (m, 1F), 67.42 (d, J = 145.7Hz, 4F).

[0063] Example 4

[0064] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3c.

[0065]

[0066] R f =0.50 (petroleum ether / ethyl acetate=20:1), white solid, yield 59%;

[0067] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ7.96 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 4.68–4.58 (m, 2H), 4.33–4.22 (m, 1H), 1.55 (s, 3H), 1.52 (s, 3H), 1.35 (s, 9H). 13 C NMR (151MHz, CDCl3) δ196.7, 158.1, 134.3, 128.8, 126.1, 71.7 (p, J = 14.2Hz), 70.1, 52.8, 35.4, 33.6, 31.2, 28.3. 19 F NMR (565MHz, CDCl3) δ85.13–83.43 (m, 1F), 67.45 (d, J = 145.5Hz, 4F).

[0068] Example 5

[0069] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3d.

[0070]

[0071] R f =0.50 (petroleum ether / ethyl acetate=20:1), white solid, yield 51%;

[0072] Its NMR data are: 1 H NMR(600MHz, CDCl3)δ7.93(d,J=8.1Hz,2H),7.29–7.26(m,2H),4.70–4.54(m,2H),4.31–4.19(m ,1H),2.55(d,J=7.2Hz,2H),1.98–1.85(m,1H),1.54(s,3H),1.52(s,3H),0.92(d,J=6.6Hz,6H). 13 C NMR (151MHz, CDCl3) δ196.8,148.9,134.8,129.8,128.8,72.0–71.4(m),70.0,52.8,45.6,33.5,30.2,28.3,22.5. 19 F NMR (565MHz, CDCl3) δ84.39 (p, J = 145.4Hz, 1F), 67.49 (d, J = 148.8Hz, 4F).

[0073] Example 6

[0074] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3e.

[0075]

[0076] R f =0.40 (petroleum ether / ethyl acetate=20:1), white solid, yield 76%;

[0077] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ8.05(d,J=8.4Hz,2H),7.78(d,J=8.2Hz,2H),4.66–4.51(m,2H),4.30–4.15(m,1H),1.56(s,3H),1.52(s,3H). 13C NMR (151MHz, CDCl3) δ196.5, 138.2, 135.8, 131.5, 129.5, 129.3 (q, J = 308.5Hz), 71.7–71.1 (m), 69.3, 53.0, 32.9, 28.6. 19 F NMR (565MHz, CDCl3) δ84.84–82.78 (m, 1F), 67.41 (d, J = 145.7Hz, 4F), -41.39 (d, J = 9.0Hz, 3F).

[0078] Example 7

[0079] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3f.

[0080]

[0081] R f =0.50 (petroleum ether / ethyl acetate=5:1), white solid, yield 77%;

[0082] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ8.11(d,J=7.0Hz,2H),7.74(d,J=6.9Hz,2H),7.64(d,J=7.1Hz,2H),7.57–7. 46(m,2H),7.43(d,J=6.8Hz,1H),4.82–4.54(m,2H),4.47–4.20(m,1H),1.58(s,3H),1.57(s,3H). 13 C NMR (151MHz, CDCl3) δ196.7,146.9,139.7,135.6,129.5,129.2,128.7,127.7,127.5,71.9–71.4(m),69.9,52.9,33.4,28.4. 19 F NMR (565MHz, CDCl3) δ85.04–83.53 (m, 1F), 67.50 (d, J = 145.4Hz, 4F).

[0083] Example 8 Synthesis of 3g of β-SF5-ketone compound

[0084] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3g.

[0085]

[0086] R f=0.70 (petroleum ether / ethyl acetate=20:1), white solid, yield 58%;

[0087] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ8.12–8.02(m,2H),7.24–7.13(m,2H), δ4.72–4.50(m,2H),4.30–4.18(m,1H),1.55(s,3H),1.52(s,3H). 13 C NMR (151MHz, CDCl3) δ 195.7, 166.4 (d, J = 257.2Hz), 133.4, 131.6 (d, J = 9.5Hz), 116.3 (d, J = 22.0Hz), 71.6 (p, J = 14.4Hz), 69.6, 52.9, 33.1, 28.5. 19 F NMR (565MHz, CDCl3) δ84.76–83.57 (m, 1F), 67.41 (d, J = 144.0Hz, 4F), -103.39 (s, 1F).

[0088] Example 9

[0089] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3h.

[0090]

[0091] R f =0.70 (petroleum ether / ethyl acetate=20:1), white solid, yield 54%;

[0092] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ7.97(d,J=8.3Hz,2H),7.49(d,J=8.3Hz,2H),4.68–4.50(m,2H),4.30–4.17(m,1H),1.55(s,3H),1.51(s,3H). 13 C NMR (151MHz, CDCl3) δ196.1,140.8,135.3,130.2,129.5,71.8–71.3(m),69.5,52.9,33.1,28.5. 19 F NMR (565MHz, CDCl3) δ85.00–83.34 (m, 1F), 67.39 (d, J = 144.0Hz, 4F).

[0093] Example 10

[0094] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3i.

[0095]

[0096] R f =0.70 (petroleum ether / ethyl acetate=20:1), white solid, yield 61%;

[0097] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ7.89(d,J=8.5Hz,2H),7.66(d,J=8.5Hz,2H),4.63–4.55(m,2H),4.27–4.18(m,1H),1.55(s,3H),1.51(s,3H). 13 C NMR (151MHz, CDCl3) δ196.3,135.7,132.5,130.3,129.6,71.8–71.2(m),69.5,52.8,33.0,28.5. 19 F NMR (565MHz, CDCl3) δ85.00–83.34 (m, 1F), 67.04 (d, J = 145.1Hz, 4F).

[0098] Example 11

[0099] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3j.

[0100]

[0101] R f =0.30 (petroleum ether / ethyl acetate=20:1), white solid, yield 75%;

[0102] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ7.97(d,J=8.4Hz,2H),7.49(d,J=8.4Hz,2H),4.78–4.51(m,2H),4.35–4.12(m,1H),1.55(s,3H),1.51(s,3H). 13 C NMR (151MHz, CDCl3) δ196.2, 139.8, 132.9, 129.1, 117.8, 117.3, 71.3 (p, J = 14.4Hz), 68.9, 53.0, 32.3, 29.0. 19 FNMR (565MHz, CDCl3) δ84.78–83.17 (m, 1F), 67.43 (d, J = 145.6, 4F).

[0103] Example 12

[0104] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3k.

[0105]

[0106] R f =0.50 (petroleum ether / ethyl acetate=5:1), white solid, yield 63%;

[0107] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ7.96 (d, J=7.8Hz, 1H), 7.85 (s, 1H), 7.61–7.55 (m, 1H), 7.48 (d,J=8.1Hz,1H),4.65–4.55(m,2H),4.29–4.17(m,1H),1.57(s,3H),1.52(s,3H). 13 C NMR (151MHz, CDCl3) δ195.9, 150.0, 138.8, 130.7, 127.0, 126.3, 121.1, 120.7 (q, J = 258.5Hz), 71.5 (p, J = 14.1Hz), 69.2, 53.1, 32.9, 28.7. 19 F NMR (565MHz, CDCl3) δ85.06–82.51 (m, 1F), 67.38 (d, J = 145.7Hz, 4F), -57.98 (s, 3F).

[0108] Example 13

[0109] Referring to the synthetic method of Example 2, the substituent of the substrate was changed to obtain compound 31.

[0110]

[0111] R f =0.30 (petroleum ether / ethyl acetate=20:1), white solid, yield 64%;

[0112] Its NMR data are: 1 H NMR(600MHz, CDCl3)δ7.81(d,J=7.8Hz,1H),7.70(d,J=9.4Hz,1H),7.55–7.47(m,1H) ,7.37–7.30(m,1H),4.67–4.50(m,2H),4.33–4.16(m,1H),1.55(s,3H),1.52(s,3H). 13C NMR (151MHz, CDCl3) δ196.1, 163.2 (d, J = 249.2Hz), 139.1 (d, J = 5.4Hz), 130.8 (d, J = 7.6Hz) ,124.6,121.2(d,J=21.6Hz),115.5(d,J=22.8Hz),71.7–71.2(m),69.4,53.1,33.0,28.5. 19 F NMR (565MHz, CDCl3) δ84.71–83.30 (m, 1F), 67.45 (dt, J=145.6, 7.5Hz, 4F), -110.93–-111.04 (m, 1F).

[0113] Example 14

[0114] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3m.

[0115]

[0116] R f =0.50 (petroleum ether / ethyl acetate=20:1), oily liquid, yield 63%;

[0117] Its NMR data are: 1 H NMR(600MHz, CDCl3)δ7.91(d,J=7.8Hz,1H),7.58–7.50(m,1H),7.10–6.99(m,2H),5.26(d,J =10.6Hz,1H),4.75–4.61(m,1H),4.25–4.14(m,1H),4.00(s,3H),1.59(s,3H),1.53(s,3H). 13 C NMR (151MHz, CDCl3) δ196.9,159.3,135.2,131.7,127.1,121.2,112.7,71.6–71.0(m),70.4,56.7,55.9,32.5,28.8. 19 F NMR (565MHz, CDCl3) δ85.58–84.07 (m, 1F), 67.26 (dt, J = 145.3, 7.7Hz, 4F).

[0118] Example 15

[0119] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3n.

[0120]

[0121] Rf =0.30 (petroleum ether / ethyl acetate=20:1), white solid, yield 61%;

[0122] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ7.74–7.62(m,2H),4.58–4.48(m,1H),4.44(d,J=10.8Hz,1H),4.25–4.11(m,1H),1.58(s,3H),1.53(s,3H). 13 C NMR (151MHz, CDCl3) δ194.2,153.1–149.8(m),145.5–141.9(m),132.6,114.0–112.5(m),72.0–70.8(m),68.8,52.8,32.3,29.0. 19 F NMR (565MHz, CDCl3) δ84.65–82.84 (m, 1F), 67.41 (d, J = 145.6Hz, 4F), -128.17–-134.05 (m, 3F).

[0123] Example 16

[0124] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3o.

[0125]

[0126] R f =0.50 (petroleum ether / ethyl acetate=5:1), white solid, yield 63%;

[0127] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ6.88(s,2H),5.03–4.87(m,1H),4.28(d,J=7.2Hz,1H),4.23–4.10(m,1H),2.36(s,6H),2.29(s,3H),1.58(s,3H),1.43(s,3H). 13 CNMR(151MHz, CDCl3)δ200.9,140.7,137.8,135.9,130.6,70.3,69.4–69.0(m),60.2,34.0,30.8,21.2. 19 F NMR (565MHz, CDCl3) δ86.58–84.73 (m, 1F), 67.45 (dt, J = 145.4, 7.8Hz, 4F).

[0128] Example 17

[0129] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3p.

[0130]

[0131] R f =0.50 (petroleum ether / ethyl acetate=20:1), white solid, yield 83%;

[0132] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ7.86(d,J=1.4Hz,2H),7.61(s,1H),4.62–4.50(m,1H),4.47(d,J=10.9Hz,1H),4.23–4.14(m,1H),1.57(s,3H),1.53(s,3H). 13 C NMR (151MHz, CDCl3) δ195.1, 139.4, 136.3, 133.8, 127.1, 71.3 (p, J = 14.3Hz), 68.9, 53.2, 32.6, 28.9. 19 F NMR (565MHz, CDCl3) δ84.88–82.57 (m, 1F), 67.52 (dt, J = 145.5, 7.4Hz, 4F).

[0133] Example 18

[0134] Referring to the synthetic method of Example 2, the substituent of the substrate was changed to obtain compound 3q.

[0135]

[0136] R f =0.450 (petroleum ether / ethyl acetate=10:1), white solid, yield 80%;

[0137] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ7.99(d,J=8.0Hz,2H),7.94(d,J=8.0Hz,2H),4.68–4.58(m,2H),4.31–4.20(m,1H),1.54(s,3H),1.50(s,3H),1.36(s,12H). 13 C NMR (151MHz, CDCl3) δ197.4,138.7,135.4,127.8,84.5,72.2–71.1(m),69.8,52.9,33.4,28.4,25.1,25.0. 19F NMR (565MHz, CDCl3) δ85.15–83.16 (m, 1F), 67.42 (d, J = 146.0Hz, 4F).

[0138] Example 19

[0139] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3r.

[0140]

[0141] R f =0.20 (petroleum ether / ethyl acetate=20:1), white solid, yield 61%;

[0142] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ8.05(d,J=8.6Hz,2H),7.67(d,J=8.3Hz,2H),7.17(d,J=8.2Hz,2H) ,7.09(d,J=8.6Hz,2H),4.69–4.46(m,2H),4.31–4.16(m,1H),1.57(s,3H),1.54(s,3H). 13 C NMR (151MHz, CDCl3) δ195.6,161.6,158.4,132.5,131.3,127.7(q,J=6.9,3.2Hz),127.0(q, J=32.7Hz),124.1(q,J=272.0Hz),120.1,118.5,71.7(p,J=14.1Hz),69.8,52.8,33.2,28.5. 19 F NMR (565MHz, CDCl3) δ85.34–82.81 (m, 1F), 67.43 (d, J = 146.1Hz, 4F), -62.03 (s, 3F).

[0143] Example 20

[0144] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3s.

[0145]

[0146] R f =0.70 (petroleum ether / ethyl acetate=5:1), white solid, yield 63%;

[0147] Its NMR data are: 1H NMR (600MHz, CDCl3) δ8.13(d,J=8.6Hz,2H),8.03(m,1H),7.87(d,J=8.6Hz,2H),7.78 (s,1H),6.53(s,1H),4.69–4.58(m,2H),4.31–4.20(m,1H),1.57(s,3H),1.54(s,3H). 13 C NMR (151MHz, CDCl3) δ195.9,144.1,142.5,134.4,130.6,127.0,118.8,109.0,71.9–71.3(m),69.7,52.8,33.2,28.4. 19 F NMR (565MHz, CDCl3) δ84.86–83.40 (m, 1F), 67.45 (d, J = 145.5Hz, 4F).

[0148] Example 21

[0149] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3t.

[0150]

[0151] R f =0.60 (petroleum ether / ethyl acetate=20:1), white solid, yield 45%;

[0152] Its NMR data are: 1 H NMR(600MHz, CDCl3)δ8.18(d,J=1.6Hz,1H),7.60(d,J=5.0Hz,1H),7.41–7.33(m,1H),4 .65–4.51(m,1H),4.36(d,J=10.7Hz,1H),4.31–4.14(m,1H),1.57(s,3H),1.56(s,3H). 13 C NMR (151MHz, CDCl3) δ191.1, 142.3, 133.8, 127.3, 127.2, 71.4 (p, J = 14.3Hz), 69.8, 55.9–55.3 (m), 33.4, 28.2. 19 F NMR (565MHz, CDCl3) δ84.80–83.36 (m, 1F), 66.97 (d, J = 145.4Hz, 4F).

[0153] Example 22

[0154] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3u.

[0155]

[0156] R f =0.30 (petroleum ether / ethyl acetate=20:1), white solid, yield 77%;

[0157] Its NMR data are: 1 H NMR(600MHz, CDCl3)δ8.83(s,1H),8.33(d,J=7.9Hz,1H),7.78–7.70(m,1H),7.56–7.48(m,2 H),5.81(d,J=11.0Hz,1H),4.63–4.46(m,1H),4.12–3.97(m,1H),1.72(s,3H),1.63(s,3H). 13 C NMR (151MHz, CDCl3) δ195.9, 175.2, 164.0, 155.8, 134.8, 126.9, 126.8, 125.6, 121.0, 118.4, 71.1 (p, J = 14.4Hz), 69.6, 54.3, 31.3, 29.7. 19 F NMR (565MHz, CDCl3) δ85.69–83.65 (m, 1F), 67.50 (d, J = 145.6Hz, 4F).

[0158] Example 23

[0159] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3v.

[0160]

[0161] R f =0.30 (petroleum ether / ethyl acetate=20:1), white solid, yield 38%;

[0162] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ7.50–7.41(m,5H),7.25(d,J=2.9Hz,1H),4.16–4.03( m,1H),3.85(d,J=11.1Hz,1H),3.82–3.72(m,1H),1.40(s,3H),1.29(s,3H). 13 CNMR(151MHz, CDCl3)δ204.2,141.8,132.9,131.4,131.1,130.3,129.5,67.9–67.4(m),61.7,45.5,23.1,17.1. 19F NMR (565MHz, CDCl3) δ85.21–83.92 (m, 1F), 64.37 (d, J = 145.2Hz, 4F).

[0163] Example 24

[0164] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3w.

[0165]

[0166] R f =0.70 (petroleum ether / ethyl acetate=5:1), white solid, yield 60%;

[0167] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ7.90–7.87(m,2H),7.77–7.74(m,2H),4.82–4.65(m,2H),4.43 –4.26(m,1H),4.25–4.06(m,1H),3.81(d,J=10.8Hz,1H),1.89(s,3H),1.55(s,3H). 13 C NMR (151MHz, CDCl3) δ199.8,167.5,134.4,132.2,123.8,71.7–70.4(m),68.7,56.4,48.7,32.4,28.4. 19 F NMR (565MHz, CDCl3) δ85.95–81.43 (m, 1F), 67.23 (d, J = 145.3Hz, 4F).

[0168] Example 25

[0169] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3x.

[0170]

[0171] R f =0.60 (petroleum ether / ethyl acetate=20:1), white solid, yield 68%;

[0172] Its NMR data are: 1H NMR (600MHz, CDCl3) δ4.68(d,J=9.1Hz,1H),3.96–3.77(m,2H),2.83–2.70(m,1H),1.84–1.75(m,2H),1.70(d,J=8 .2Hz,2H),1.67–1.62(m,1H),1.50–1.41(m,1H),1.41–1.33(m,1H),1.31(s,3H),1.27(s,3H),1.26–1.19(m,3H). 13 C NMR (151MHz, CDCl3) δ214.2,74.7 (p, J=14.1Hz), 60.1, 52.5, 45.2, 29.1, 28.8, 24.8, 24.7, 24.7, 21.2, 19.1. 19 F NMR (565MHz, CDCl3) δ84.17–82.29 (m, 1F), 65.80 (d, J = 146.9Hz, 4F).

[0173] Example 26

[0174] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3y.

[0175]

[0176] R f =0.50 (petroleum ether / ethyl acetate=5:1), white solid, yield 72%;

[0177] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ4.49–4.33(m,1H),3.97–3.88(m,1H),3.87(d,J=10.0Hz,1H),2.76(t,J=11.2Hz,1H),2.27–2.14(m,2H ),2.13–2.07(m,1H),2.00–1.93(m,1H),1.92–1.83(m,1H),1.82–1.65(m,2H),1.64–1.62(m,1H),1.61(s,3H),1.59(s,3H). 13 C NMR(151MHz, CDCl3)δ209.3,122.5(t,J=240.87Hz),71.5–70.7(m),68.9,57.5(t,J=3.4Hz),50 .4,33.2(t,J=24.46Hz),32.8(t,J=24.88Hz),31.0,30.1,25.5(d,J=9.7Hz),24.5(d,J=9.4Hz).19 F NMR (565MHz, CDCl3) δ86.36–81.25(m,1F),67.42–67.06(m,4F),-87.94–-95.89(m,1F),-99.71–-105.47(m,1F).

[0178] Example 27

[0179] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3z.

[0180]

[0181] R f =0.50 (petroleum ether / ethyl acetate=40:1), white solid, yield 53%;

[0182] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ4.54–4.31(m,1H),4.10–3.94(m,1H),3.85(d,J=10.2Hz,1H),3.20–3.08(m,1H),1.98(dd,J =24.9,14.1Hz,1H),1.93–1.83(m,2H),1.83–1.74(m,2H),1.68(d,J=14.9Hz,3H),1.66–1.56(m,3H),1.54(s,3H). 13 C NMR (151MHz, CDCl3) δ212.6,71.5–70.8(m),69.4,59.7,54.3,32.8,32.1,30.8,29.1,26.7,26.0. 19 F NMR (565MHz, CDCl3) δ85.51–83.70 (m, 1F), 67.11 (dt, J = 146.2, 7.6Hz, 4F)

[0183] Example 28

[0184] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3aa.

[0185]

[0186] R f =0.90 (petroleum ether / ethyl acetate=20:1), white solid, yield 67%;

[0187] Its NMR data are: 1H NMR (600MHz, CDCl3) δ8.06–7.90(m,2H),7.65–7.55(m,1H),7.53–7.46(m,2H),4.77–4.61(m,2H),4.09–4.01(m,1H),1. 81–1.73(m,1H),1.73–1.64(m,2H),1.61–1.50(m,2H),1.50–1.35(m,3H),0.85(t,J=7.2Hz,3H),0.72(t,J=7.3Hz,3H). 13 C NMR (151MHz, CDCl3) δ197.9,137.8,133.7,128.9,128.6,72.0–71.4(m),49.3,41.4,41.2,18.0,17.6,14.1,13.9. 19 F NMR (565MHz, CDCl3) δ85.00–83.66 (m, 1F), 67.23 (d, J = 145.1Hz, 4F).

[0188] Example 29

[0189] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3ab.

[0190]

[0191] R f =0.50 (petroleum ether / ethyl acetate=20:1), white solid, yield 71%;

[0192] Its NMR data are: 1 H NMR(600MHz, CDCl3)δ8.03(d,J=7.7Hz,2H),7.63(s,1H),7.57–7.39(m,2H),4.75–4.56(m,2H),4.41–4.24( m,1H),2.01–1.88(m,1H),1.80–1.55(m,6H),1.52–1.46(m,1H),1.26(t,J=13.1Hz,1H),1.08–0.95(m,1H). 13 C NMR (151MHz, CDCl3) δ197.3, 137.1, 134.0, 129.1, 128.8, 76.5, 71.4 (p, J = 14.1Hz), 53.6, 40.1, 34.2, 24.7, 22.1, 21.5. 19 F NMR (565MHz, CDCl3) δ85.55–83.64 (m, 1F), 67.49 (d, J = 145.7Hz, 4F).

[0193] Example 30

[0194] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3ac.

[0195]

[0196] R f =0.50 (petroleum ether / ethyl acetate=40:1), white solid, yield 71%;

[0197] Its NMR data are: 1 H NMR(600MHz, CDCl3)δ8.01(d,J=7.5Hz,2H),7.66–7.60(m,1H),7.55–7.44(m,2H),4.81–4.64(m,2 H),4.33–4.18(m,1H),2.13–2.05(m,1H),1.99–1.84(m,3H),1.84–1.74(m,1H),1.73–1.55(m,3H). 13 C NMR (151MHz, CDCl3) δ196.4,136.9,134.1,129.2,128.7,81.3,71.8–71.0(m),51.3,42.4,38.3,22.5,22.2. 19 F NMR (565MHz, CDCl3) δ85.35–83.49 (m, 1F), 66.96 (dt, J = 145.3, 7.3Hz, 4F).

[0198] Example 31

[0199] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 3ad.

[0200]

[0201] R f =0.40 (petroleum ether / ethyl acetate=5:1), white solid, yield 58%;

[0202] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ8.11(d,J=8.2Hz,2H),8.06(d,J=8.3Hz,2H),4.63(dt,J=13.0,8.8Hz, 2H),4.33–4.15(m,1H),3.62–3.46(m,1H),1.56(s,3H),1.52(s,3H),1.24(d,J=6.8Hz,6H).13 C NMR (151MHz, CDCl3) δ203.8, 196.8, 140.4, 139.8, 129.0, 128.9, 71.5 (p, J = 14.3Hz), 69.3, 53.2, 36.1, 32.9, 28.7, 19.1. 19 F NMR (565MHz, CDCl3) δ84.81–83.23 (m, 1F), 67.48 (dt, J = 145.7, 6.7Hz, 4F).

[0203] Example 32

[0204] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 4a.

[0205]

[0206] R f =0.50 (petroleum ether / ethyl acetate=5:1), colorless transparent liquid, yield 70%;

[0207] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ8.17(d,J=7.9Hz,2H),8.08(d,J=8.0Hz,2H),5.02–4.91(m,1H),4.68–4.56(m,2H),4.29–4.19(m,1H),2.13(d,J=11.9H z,1H),2.00–1.91(m,1H),1.74(d,J=11.1Hz,2H),1.56(s,6H),1.51(s,3H),1.19–1.07(m,2H),0.93(t,J=6.2Hz,6H),0.80(d,J=6.9Hz,3H). 13 C NMR(151MHz, CDCl3).δ196.9,165.1,139.9,135.6,130.2,128.7,75.9,71.9–71.7 (m),69.4,53.1,47.4,41.1,34.4,33.0,31.6,28.6,26.7,23.8,22.2,20.9,16.7. 19 F NMR (565MHz, CDCl3) δ85.04–83.25 (m, 1F), 67.50 (d, J = 145.3Hz, 4F).

[0208] Example 33

[0209] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 4b.

[0210]

[0211] R f =0.50 (petroleum ether / ethyl acetate=20:1), white solid, yield 58%;

[0212] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ8.19(d,J=8.2Hz,2H),8.10(d,J=8.1Hz,2H),5.14(d,J=9.6 Hz,1H),4.69–4.52(m,2H),4.30–4.13(m,1H),2.54–2.42(m,1H),2.17–2.03(m,1H ),1.82(t,J=11.9Hz,1H),1.76(t,J=3.8Hz,1H),1.56(s,3H),1.51(s,3H),1.43( t,J=11.8Hz,1H),1.34–1.27(m,1H),1.14–1.10(m,1H),0.97(s,3H),0.92(s,6H). 13 CNMR(151MHz,CDCl3)δ196.9,165.8,140.0,135.6,130.2,128.7,81.5,71.7–71.2 (m),69.3,53.1,49.3,48.1,45.2,37.1,32.9,28.6,28.2,27.6,19.8,19.0,13.7. 19 F NMR (565MHz, CDCl3) δ85.03–83.26 (m, 1F), 67.43 (d, J = 145.5Hz, 4F).

[0213] Example 34

[0214] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 4c.

[0215]

[0216] R f =0.30 (petroleum ether / ethyl acetate=1:1), white solid, yield 77%;

[0217] Its NMR data are: 1H NMR (600MHz, CDCl3) δ8.16(d,J=8.6Hz,3H),8.08(d,J=8.2Hz,2H),8.00(d,J=8.4Hz,1H),7.91(d,J=8.4Hz,1H),4.68 –4.52(m,2H),4.49–4.35(m,2H),4.32–4.13(m,1H),3.45(s,2H),1.89(s,4H),1.56(s,3H),1.55(s,6H),1.50(s,3H). 13 C NMR (151MHz, CDCl3) δ196.8,174.6,165.5,153.1,140.2,136.6,135.4,134.8,133.8(q,J=66.5,32.9Hz),130.2,128.7,128 .0,123.1(q,J=9.5,4.7Hz),121.2,115.1,108.5,71.8–71.2(m),69.3,64.8,62.0,53.1,40.1,32.8,28.7,26.5,26.3,23.7. 19 F NMR (565MHz, CDCl3) δ84.74–83.44 (m, 1F), 67.45 (d, J = 145.5Hz, 4F), -62.04 (s, 3F).

[0218] Example 35

[0219] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 4d.

[0220]

[0221] R f =0.25 (petroleum ether / ethyl acetate=20:1), white solid, yield 58%;

[0222] Its NMR data are: 1 H NMR(600MHz, CDCl3)δ8.05(d,J=8.4Hz,2H),7.22(d,J=8.5Hz,2H),4.61(s,2H),4.34 –4.16(m,1H),2.10(s,3H),2.06(s,6H),1.85–1.69(m,6H),1.54(s,3H),1.51(s,3H). 13C NMR (151MHz, CDCl3) δ196.0,175.5,155.9,134.1,130.4,122.3,71.8–71.5(m),69.8,52.8,41.4,38.8,36.5,33.4,28.3,28.0. 19 F NMR (565MHz, CDCl3) δ85.03–83.50 (m, 1F), 67.43 (d, J = 145.6Hz, 4F).

[0223] Example 36

[0224] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 4e.

[0225]

[0226] R f =0.25 (petroleum ether / ethyl acetate=20:1), white solid, yield 55%;

[0227] Its NMR data are: 1 H NMR(600MHz, CDCl3)δ8.01(d,J=8.6Hz,2H),7.29(d,J=7.8Hz,2H),7.19–7.12(m,4H),4.58(s,2H),4.32–4.15(m,1H),4.00–3 .89(m,1H),2.47(d,J=7.2Hz,2H),1.93–1.80(m,1H),1.62(d,J=7.1Hz,3H),1.53(s,3H),1.49(s,3H),0.91(d,J=6.6Hz,6H). 13 C NMR (151MHz, CDCl3) δ195.9,172.6,155.5,141.3,136.9,134.3,130.4,129.8,12 7.4,122.1,71.9–71.4(m),69.7,52.9,45.5,45.2,33.3,30.3,28.4,22.5,18.5. 19 F NMR (565MHz, CDCl3) δ84.15 (p, J = 146.3Hz, 1F), 67.39 (d, J = 146.1Hz, 4F).

[0228] Example 37

[0229] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 4f.

[0230]

[0231] R f =0.25 (petroleum ether / ethyl acetate=20:1), white solid, yield 40%;

[0232] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ8.34(d,J=8.4Hz,2H),8.17(d,J=8.4Hz,2H),7.73(d,J=9.6Hz,1H),7.57(d,J=8.4Hz,1H),7.27(d,J=1.8Hz,1H ),7.23–7.15(m,1H),6.44(d,J=9.6Hz,1H),4.68(d,J=10.9Hz,1H),4.66–4.56(m,1H),4.30–4.16(m,1H),1.60(s,3H),1.54(s,3H). 13 C NMR (151MHz, CDCl3) δ196.8,163.6,160.3,154.9,153.3,142.9,140.9,133.4,131. 0,128.9,128.9,118.5,117.2,116.5,110.7,71.6–70.9(m),69.2,53.2,32.7,28.8. 19 F NMR (565MHz, CDCl3) δ84.69–83.28 (m, 1F), 67.51 (dt, J = 146.5, 7.1Hz, 4F).

[0233] Example 38

[0234] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 4g.

[0235]

[0236] R f =0.50 (petroleum ether / ethyl acetate=5:1), white solid, yield 50%;

[0237] Its NMR data are: 1H NMR (600MHz, CDCl3) δ8.36(d,J=8.3Hz,2H),8.18(d,J=8.3Hz,2H),8.08(d,J=2.7Hz,1H),7.95(d,J=6.5Hz,2H),7.68(d,J=9.0Hz,1H), 7.63–7.58(m,1H),7.58–7.52(m,3H),6.85(s,1H),4.72–4.67(m,1H),4.67–4.58(m,1H),4.31–4.19(m,1H),1.60(s,3H),1.55(s,3H). 13 C NMR (151MHz, CDCl3) δ196.8,177.7,164.0,163.9,154.1,147.8,140.8,133.6,132.0,131.7,130. 9,129.3,128.9,127.9,126.5,125.0,119.8,118.0,107.4,71.7–71.1(m),69.2,53.2,32.8,28.7. 19 F NMR (565MHz, CDCl3) δ84.78–83.33 (m, 1F), 67.51 (d, J = 145.4Hz, 4F).

[0238] Example 39

[0239] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 4h.

[0240]

[0241] R f =0.50 (petroleum ether / ethyl acetate=5:1), white solid, yield 70%;

[0242] Its NMR data are: 1H NMR (600MHz, CDCl3) δ8.16(d,J=8.1Hz,2H),8.06(d,J=8.0Hz,2H),5.03–4.93(m,1H),4.67–4.56(m ,2H),4.31–4.17(m,1H),2.44(dd,J=19.4,8.7Hz,1H),2.15–2.02(m,1H),2.02–1.88(m,2H),1.86– 1.74(m,4H),1.73–1.61(m,2H),1.62–1.57(m,2H),1.56(s,3H),1.50(s,3H),1.42–1.32(m,3H),1. 32–1.22(m,4H),1.17–1.08(m,1H),1.07–0.96(m,1H),0.91(s,3H),0.87(s,3H),0.80–0.73(m,1H). 13 C NMR (151MHz, CDCl3) δ196.9,165.1,139.9,135.6,130.2,128.6,75.1,72.0–70.5(m),69.4,54.5,53.1,5 1.6,47.9,44.9,36.9,36.0,35.9,35.2,34.1,33.0,31.7,31.0,28.6,28.5,27.6,21.9,20.7,14.0,12.4. 19 F NMR (565MHz, CDCl3) δ84.98–83.39 (m, 1F), 67.47 (d, J = 145.4Hz, 4F).

[0243] Example 40

[0244] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 4i.

[0245]

[0246] R f =0.30 (petroleum ether / ethyl acetate=10:1), white solid, yield 52%;

[0247] Its NMR data are: 1H NMR (600MHz, CDCl3) δ8.16 (d, J = 8.0Hz, 2H), 8.08 (d, J = 8.1Hz, 2H), 5.74 (s, 1H), 4.88 (t, J = 8. 3Hz,1H),4.70–4.55(m,2H),4.28–4.18(m,1H),2.50–2.38(m,2H),2.37–2.27(m,3H),2.03(d, J=13.1Hz,1H),1.88(d,J=11.2Hz,2H),1.79–1.58(m,5H),1.56(s,3H),1.51(s,3H),1.48–1. 41(m,2H),1.32–1.24(m,2H),1.21(s,3H),1.19–1.12(m,1H),1.11–1.03(m,1H),0.99(s,3H). 13 C NMR (151MHz, CDCl3) δ199.5,196.9,170.8,165.4,140.0,135.3,130.2,128.7,124.2,83.8,71.9–70.8(m),69 .3,53.9,53.1,50.5,43.1,38.8,36.9,35.9,35.6,34.1,32.9,32.9,31.7,28.6,27.8,23.8,20.7,17.6,12.5. 19 FNMR (565MHz, CDCl3) δ84.77–83.31 (m, 1F), 67.44 (d, J = 145.3Hz, 4F).

[0248] Example 41

[0249] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 4j.

[0250]

[0251] R f =0.30 (petroleum ether / ethyl acetate=20:1), white solid, yield 30%;

[0252] Its NMR data are: 1H NMR (600MHz, CDCl3) δ8.16(d,J=8.0Hz,2H),8.06(d,J=8.0Hz,2H),5.01–4.91(m,1H),4. 68–4.55(m,2H),4.31–4.16(m,1H),1.96(t,J=14.7Hz,2H),1.80(d,J=14.1Hz,2H),1.73 (d,J=11.7Hz,1H),1.70–1.61(m,2H),1.55(s,5H),1.50(s,5H),1.42–1.20(m,12H),1.1 8–1.05(m,6H),1.04–0.95(m,3H),0.90(d,J=6.1Hz,5H),0.88–0.85(m,8H),0.66(s,3H). 13 C NMR (151MHz, CDCl3) δ196.9,165.1,139.9,135.7,130.2,128.6,75.4,71.8–71.0(m),69.4,56.6,56.5,54.4,53.2,44.9,42.8,4 0.2,39.7,37.0,36.4,36.0,35.7,34.2,33.0,32.2,28.8,28.6,28.4,28.2,27.7,24.4,24.0,23.0,22.7,21.4,18.8,12.5,12.2. 19 FNMR (565MHz, CDCl3) δ84.84–83.35 (m, 1F), 67.45 (d, J = 145.4Hz, 4F).

[0253] Example 42

[0254] Referring to the synthesis method of Example 2, the substituent of the substrate was changed to obtain compound 4k.

[0255]

[0256] R f =0.30 (petroleum ether / ethyl acetate=10:1), white solid, yield 52%;

[0257] Its NMR data are: 1H NMR (600MHz, CDCl3) δ8.17(d,J=8.2Hz,2H),8.08(d,J=8.2Hz,2H),5.03–4.92(m,1H),4.72–4.58(m,2H),4. 47–4.37(m,1H),4.34–4.17(m,1H),3.54–3.43(m,1H),3.40(t,J=11.0Hz,1H),2.05–1.94(m,2H),1.88(dd, J=14.0,7.1Hz,1H),1.85–1.72(m,4H),1.72–1.61(m,4H),1.57(s,6H),1.51(s,6H),1.38–1.23(m,6H),1.2 1–1.08(m,3H),0.99(d,J=6.9Hz,3H),0.97–0.93(m,1H),0.92(s,3H),0.83–0.79(m,5H),0.77–0.70(m,1H). 13 C NMR (151MHz, CDCl3) δ196.9,165.1,139.9,135.7,130.2,128.6,109.4,81.0,75.2,71.8–71.0(m),69.4,67.0,62.4,56.4,54.4,53. 1,44.9,41.8,40.7,40.2,36.9,35.8,35.3,34.2,33.0,32.3,31.9,31.6,30.5,29.0,28.7,28.6,27.7,21.2,17.3,16.6,14.7,12.5. 19 F NMR (565MHz, CDCl3) 84.06 (p, J = 145.9Hz, 1F), 67.44 (d, J = 145.8Hz, 4F).

[0258] Example 43

[0259] In a glove box, 3ad (162.4 mg, 0.4 mmol, 1.0 equiv) and tetrahydrofuran (1.5 mL, 0.3 M) were added to a 5 mL reaction flask equipped with a stirrer. Methylmagnesium bromide (0.26 mL, 0.80 mmol, 3.0 M tetrahydrofuran solution, 2.0 equiv) was then added at 0°C. The reaction mixture was stirred at room temperature for 12 hours. Thereafter, the reaction was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane (3 × 3.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure on a rotary evaporator. Further purification was performed by silica gel column chromatography to obtain compound 5.

[0260]

[0261] R f =0.30 (petroleum ether / ethyl acetate=5:1), white solid, yield 95%;

[0262] Its NMR data are: 1 H NMR(600MHz, CDCl3)δ7.98(d,J=8.3Hz,2H),7.56(d,J=8.2Hz,2H),4.76–4.47(m,2H),4.33–4.17(m,1H),2.13– 1.90(m,1H),1.64(s,1H),1.55(s,3H),1.54(s,3H),1.52(s,3H),0.93(d,J=6.7Hz,3H),0.78(d,J=6.8Hz,3H). 13 C NMR (151MHz, CDCl3) δ196.9,154.6,135.1,128.5,126.1,71.9–71.2(m),69.9,52.9,38.6,38.6,33.4,28.2,27.0,17.4,17.1. 19 F NMR (565MHz, CDCl3) δ85.43–83.13 (m, 1F), 67.47 (d, J = 145.6Hz, 4F).

[0263] Example 44

[0264] In a glove box, 3ad (162.4 mg, 0.4 mmol, 1.0 equiv) and anhydrous ethanol (0.7 mL, 0.6 M) were added to a 5 mL reaction flask equipped with a stirrer, followed by the addition of sodium borohydride (8.2 mg, 0.48 mmol, 1.2 equiv) in batches at 0°C. The reaction mixture was stirred at 100°C for 2 hours. Afterwards, the ethanol was removed by vacuum concentration and extracted with water and dichloromethane (3 × 3.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure on a rotary evaporator. Further purification was performed by silica gel column chromatography to obtain compound 6.

[0265]

[0266] R f =0.30 (petroleum ether / ethyl acetate=5:1), colorless oily liquid, yield 79%;

[0267] Its NMR data are: 1H NMR(600MHz, CDCl3)δ7.98(d,J=8.3Hz,2H),7.56(d,J=8.2Hz,2H),4.76–4.47(m,2H),4.33–4.17(m,1H),2.13– 1.90(m,1H),1.64(s,1H),1.55(s,3H),1.54(s,3H),1.52(s,3H),0.93(d,J=6.7Hz,3H),0.78(d,J=6.8Hz,3H). 13 C NMR (151MHz, CDCl3) δ196.9,154.6,135.1,128.5,126.1,71.9–71.2(m),69.9,52.9,38.6,38.6,33.4,28.2,27.0,17.4,17.1. 19 F NMR (565MHz, CDCl3) δ85.43–83.13 (m, 1F), 67.47 (d, J = 145.6Hz, 4F).

[0268] Example 45

[0269] In a glove box, a 5 mL reaction vial equipped with a stirrer was charged with 3ad (162.4 mg, 0.4 mmol, 1.0 equiv), m-chloroperbenzoic acid (487.26 mg, 2.4 mmol, 4.0 equiv., 85%), TFA (91.9 μL, 1.2 mmol, 2.0 equiv), and anhydrous dichloromethane (6.0 mL, 0.10 M). The reaction mixture was stirred at room temperature for 24 hours. The reaction was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3 x 3.0 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure on a rotary evaporator. The product was further purified by silica gel column chromatography to yield compound 7.

[0270]

[0271] R f =0.30 (petroleum ether / ethyl acetate=20:1), yellow oily liquid, yield 81%;

[0272] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ8.16(d,J=8.1Hz,2H),8.07(d,J=8.0Hz,2H),5.28(dt,J=12.1,6.1 Hz,1H),4.64(s,2H),4.31–4.17(m,1H),1.56(s,3H),1.51(s,3H),1.39(d,J=6.0Hz,6H).13 C NMR (151MHz, CDCl3) δ196.9, 165.0, 139.9, 135.6, 130.2, 128.6, 71.4 (p, J = 15.0Hz), 69.3, 53.1, 33.0, 28.6, 22.0. 19 F NMR (565MHz, CDCl3) δ84.90–83.13 (m, 1F), 67.45 (dt, J = 126.1, 6.8Hz, 4F).

[0273] Example 46

[0274] In a glove box, a 2 mL reaction vial equipped with a stirrer was charged with 3a (100.81 mg, 0.3 mmol, 1.0 equiv.), phenol (28.23 mg, 0.3 mmol, 1.0 equiv.), cesium carbonate (293.24 mg, 0.9 mmol, 3.0 equiv.), and anhydrous acetonitrile (1.2 mL, 0.25 M). The reaction mixture was stirred at 40°C for 8 hours. Afterwards, the reaction was quenched with water and extracted with dichloromethane (3 x 3.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure on a rotary evaporator. Further purification was performed by silica gel column chromatography to yield compound 8.

[0275]

[0276] R f =0.30 (petroleum ether / ethyl acetate=5:1), colorless oily liquid, yield 75%;

[0277] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ7.96 (d, J = 7.5Hz, 2H), 7.57–7.51 (m, 1H), 7.47–7.41 (m, 2H), 7.26–7. 20(m,2H),6.95–6.89(m,1H),6.85(d,J=8.2Hz,2H),4.76(s,2H),1.99(s,3H),1.69(s,3H). 13 C NMR (151MHz, CDCl3) δ199.8,158.8,141.9,138.1,133.2,131.4,129.5,129.5,128.7,121.1,115.0,65.9,23.3,20.9.

[0278] Example 47

[0279] In a glove box, a 2 mL reaction vial equipped with a stirrer was charged with 3a (100.81 mg, 0.3 mmol, 1.0 equiv.), cesium acetate (230.34 mg, 1.2 mmol, 4.0 equiv.), silver acetate (50.07 mg, 0.3 mmol, 1.0 equiv.), and anhydrous ethanol (0.6 mL, 0.50 M). The reaction mixture was stirred at 40°C for 12 hours. Afterward, the reaction was quenched with water and extracted with dichloromethane (3 x 3.0 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure on a rotary evaporator.

[0280] The product was further purified by silica gel column chromatography to obtain compound 9.

[0281]

[0282] R f =0.60 (petroleum ether / ethyl acetate=5:1), colorless oily liquid, yield 36%;

[0283] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ7.86 (d, J = 7.4Hz, 2H), 7.60–7.55 (m, 1H), 7.50–7.45 (m, 2H), 4.89–4.63 (m, 2H), 2.05 (s, 3H), 1.65 (s, 3H). 13 C NMR (151MHz, CDCl3) δ197.5, 149.1, 145.0, 137.8, 133.4, 129.5, 128.9, 71.7 (p, J = 13.4Hz), 24.9, 22.3. 19 FNMR(565MHz, CDCl3)83.18–81.94(m,1F),65.79(dt,J=144.3,7.1Hz,4F).

[0284] Example 48

[0285] In a glove box, a 10 mL reaction vial equipped with a stirrer was charged with 3a (201.62 mg, 0.6 mmol, 1.0 equiv.), tris(trimethylsilyl)silane (0.78 mL, 2.52 mmol, 4.2 equiv.), azobisisobutyronitrile (19.71 mg, 0.12 mmol, 20 mol%), and anhydrous toluene (6.0 mL, 0.10 M). The reaction mixture was stirred at 80°C for 6 hours. The reaction was then quenched with saturated ammonium chloride solution and extracted with dichloromethane (3 x 3.0 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure on a rotary evaporator. The product was further purified by silica gel column chromatography to yield compound 10.

[0286]

[0287] R f =0.30 (petroleum ether / ethyl acetate=20:1), colorless oily liquid, yield 94%;

[0288] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ8.01–7.93(m,2H),7.64–7.56(m,1H),7.54–7.46(m,2H),4.69–4.51(m,1H),4. 16–4.00(m,1H),3.84–3.63(m,1H),2.16–1.99(m,1H),1.05(d,J=6.9Hz,3H),0.84(d,J=6.9Hz,3H). 13 C NMR (151MHz, CDCl3) δ198.9, 136.4, 133.6, 129.0, 128.5, 69.8 (p, J = 13.1Hz), 48.7, 30.9, 20.9, 18.4. 19 F NMR (565MHz, CDCl3) δ86.80–83.71 (m, 1F), 66.19 (d, J = 145.0Hz, 4F).

[0289] Example 49

[0290] In a glove box, a 5 mL reaction vial equipped with a stirrer was charged with 3i (124.18 mg, 0.3 mmol, 1.0 equiv.), 4-cyanophenylboronic acid (88.23 mg, 0.6 mmol, 2.0 equiv.), tetrakistriphenylphosphine palladium (34.67 mg, 0.03 mmol, 10 mol%), sodium carbonate (82.67 mg, 0.78 mmol, 2.6 equiv.), and 1,4-dioxane (2.0 mL, 0.15 M). The reaction mixture was stirred at 90°C for 8 hours. The reaction was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3 x 3.0 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure on a rotary evaporator. The product was further purified by silica gel column chromatography to yield compound 11.

[0291]

[0292] R f =0.30 (petroleum ether / ethyl acetate=5:1), colorless oily liquid, yield 85%;

[0293] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ8.14(d,J=8.3Hz,2H),7.78(d,J=8.3Hz,2H),7.74(s,2H),7 .72(s,2H),4.70–4.58(m,2H),4.26(d,J=12.4Hz,1H),1.59(s,3H),1.56(s,3H). 13 C NMR (151MHz, CDCl3) δ196.6,144.6,144.1,136.7,133.0,129.6,128.1,128.0,118.7,112.5,71.9–71.3(m),69.6,53.0,33.1,28.6. 19 F NMR (565MHz, CDCl3) δ87.27–78.70 (m, 1F), 67.50 (dt, J = 12.8, 6.7Hz, 4F).

[0294] Example 50

[0295] In a glove box, a 5 mL reaction vial equipped with a stirrer was charged with 3i (82.79 mg, 0.2 mmol, 1.0 equiv.), BrettPhos Pd G3 (18.13 mg, 0.02 mmol, 10 mol%), cesium carbonate (97.70 mg, 0.3 mmol, 1.5 equiv.), aniline (22.8 μL, 0.25 mmol, 1.3 equiv.), and 1,4-dioxane (0.8 mL, 0.25 M). The reaction mixture was stirred at 100°C for 1 hour. The reaction was then quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (3 x 3.0 mL). The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure on a rotary evaporator. The product was further purified by silica gel column chromatography to yield compound 12.

[0296]

[0297] R f =0.50 (petroleum ether / ethyl acetate=5:1), yellow oily liquid, yield 78%;

[0298] Its NMR data are: 1 H NMR (600MHz, CDCl3) δ7.93(d,J=8.3Hz,2H),7.41–7.31(m,2H),7.21(d,J=7.8Hz,2H),7.17–7.09(m,1H),7. 00(d,J=8.2Hz,2H),6.16(s,1H),4.70–4.59(m,1H),4.56(d,J=10.6Hz,1H),4.33–4.19(m,1H),1.56(s,6H). 13 C NMR (151MHz, CDCl3) δ194.6, 149.6, 140.2, 131.4, 129.8, 128.4, 124.2, 121.6, 114.5, 71.9 (p, J = 14.1Hz), 70.6, 52.4, 33.6, 28.3. 19 F NMR (565MHz, CDCl3) δ85.32–83.69 (m, 1F), 66.95 (d, J = 145.4Hz, 4F).

[0299] Test example

[0300] 1. Tumor suppressor activity detection

[0301] The inhibitory efficacy of the synthesized compounds on different tumor cells was detected by CCK-8 cell activity assay, and irinotecan was used as a control. The results are shown in Figure 1 and Table 1.

[0302] Table 1 Inhibition of different tumor cells by different compounds

[0303]

[0304] a represents the mean ± standard deviation (SD) of three independent experiments;

[0305] b served as a positive control.

[0306] As shown in Table 1, after 48 hours of treatment with the compound, the half-maximal inhibitory concentration (IC) of the compound on liver cancer cells HepG2, colon cancer cells HCT116, cervical cancer cells Hela, prostate cancer cells PC3, lung cancer cells A549, breast cancer cells MCF-7, and myeloma cells U266 was 50 ) are generally less than 100 μM, showing a certain anti-tumor activity. Among them, compound 5 has the strongest inhibitory effect on PC3 cells, IC 50 was 6.3 μM, which was stronger than the positive control drug irinotecan ( Figure 1 ).

[0307] 2. Tumor inhibitory effect of compound 5

[0308] (1) The inhibitory effect of compound 5 on PC3 cells was tested by colony formation assay. Figure 2 .

[0309] like Figure 2 As shown, after PC3 cells were treated with 2.5 μM compound 5 for 48 hours, cell colonies grew for 14 days. The blank control group had 412 colonies, while compound 5 reduced the number of colonies to 139 and significantly reduced the colony size, indicating that compound 5 can inhibit the medium- and long-term growth of tumor cells.

[0310] (2) The inhibitory effect of compound 5 on PC3 cells was detected by scratch test. Figure 3 .

[0311] like Figure 3 As shown, when PC3 cells were treated with 2.5 μM compound 5 for 48 hours, the invasion area of tumor cells was reduced, indicating that compound 5 reduced the invasion ability of tumor cells. Tumor cell apoptosis and the production of reactive oxygen species (ROS) are important strategies for tumor suppression.

[0312] (3) The effect of compound 5 on apoptosis of PC3 cells and its effect on ROS were detected by flow cytometry. The results are shown in Figure 4 and Figure 5 .

[0313] like Figure 4As shown, when PC3 cells were treated with 2.5μM compound 5 for 48 hours, the apoptosis rate increased from 1.2% to 10.7%, indicating that compound 5 can induce apoptosis of tumor cells. In the ROS detection, when PC3 cells were treated with 2.5μM compound 3b for 48 hours, the intracellular ROS production was significantly promoted, indicating that compound 5 can induce ROS production in tumor cells and then cause oxidative stress ( Figure 5 )

[0314] (4) Using cell transcriptome sequencing technology, the changes in gene expression in PC3 cells after compound 5 were detected, and GO analysis and KEGG pathway analysis were performed. The results are shown in Figures 6-8 .

[0315] like Figure 6 As shown, treatment of PC3 cells with 2.5 μM compound 5 for 48 hours caused an increase in the expression of 1306 genes and a decrease in the expression of 1373 genes. GO analysis of biological functions of these differentially expressed genes showed that compound 5 affected the structure and function of tumor cells ( Figure 7 ); KEGG pathway analysis of differentially expressed genes showed that compound 5 was associated with classic tumor suppressor pathways such as P53, TNF, NF-kappa B, and TGF-beta ( Figure 8 ).

[0316] In summary, the compounds prepared in the present invention all showed certain anti-tumor activity, among which compound 5 had the most significant inhibitory effect on prostate cancer cells. The mechanism may be to activate tumor suppressor-related pathways, induce ROS production, cause cancer cell apoptosis, and ultimately inhibit tumor cell proliferation, survival and migration.

[0317] Finally, it should be noted that the above specific implementation methods are only used to illustrate the technical solutions of the present invention and are not limiting. Although the present invention has been described in detail with reference to examples, those skilled in the art should understand that the technical solutions of the present invention can be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A β-SF5-ketone compound, characterized in that Its structural formula is as follows: Among them, R 1 The group is an alkyl, alkene, heteroaromatic or aryl group, R 2 The group is an alkyl group.

2. The β-SF5-ketone compound according to claim 1, characterized in that The R 1 The group is selected from alkyl, alkene, heteroaromatic, aryl or aromatic groups containing different substituents; R 2 The group is methyl; The substituent is one of halogen, alkane, cyano, alkoxy, ether, isobutyryl, trifluoromethyl, trifluoromethylthio, menthol, 2-camphenol, RU 58841, adamantane carboxylic acid, ibuprofen, 7-hydroxycoumarin, 6-hydroxyflavone, dihydrocholesterol, epiandrosterone, testosterone or sisalogenin.

3. The β-SF5-ketone compound according to claim 2, characterized in that The β-SF5-ketone compound is:

4. A method for preparing the β-SF5-ketone compound according to any one of claims 1 to 3, characterized in that: The following processes are included: (1) preparing a n-hexane solution of pentafluorosulfuryl chloride having a concentration greater than 0.4 M by distillation; (2) Add β,γ-unsaturated ketone and pentafluorosulfuryl chloride n-hexane solution into a solvent, and then carry out 1,2 carbonyl migration of free radicals in the β,γ-unsaturated ketone molecule under light of wavelength of 360-365nm at 32-35℃ to prepare β-SF5-ketone compounds.

5. The preparation method according to claim 4, characterized in that The molar ratio of the beta, gamma-unsaturated ketone to pentafluorosulfuryl chlorine is 0.10:0.10-0.

12.

6. The preparation method according to claim 4 or 5, characterized in that The structural formula of the β,γ-unsaturated ketone is as follows: Among them, R 1 The group is selected from alkyl, alkene, heteroaromatic, aryl or aromatic groups containing different substituents; R 2 The group is methyl; the substituent is one of halogen, alkane, cyano, alkoxy, ether, isobutyryl, trifluoromethyl, trifluoromethylthio, menthol, 2-camphenol, RU 58841, adamantane carboxylic acid, ibuprofen, 7-hydroxycoumarin, 6-hydroxyflavone, dihydrocholesterol, epiandrosterone, testosterone or sisalogenin.

7. An improved SF5Cl synthesis method, characterized in that: The following processes are included: Under the catalysis of trifluoroacetic acid, sulfur powder, trichloroisocyanuric acid and potassium fluoride are used as raw materials, reacted in a solvent at room temperature for 14 to 16 hours, and then distilled to obtain a hexane solution of pentafluorosulfuryl chloride with a concentration greater than 0.4M.

8. Use of the β-SF5-ketone compound according to any one of claims 1 to 3 in the preparation of anti-tumor drugs.

9. The use according to claim 8, characterized in that The tumor is liver cancer, colon cancer, cervical cancer, prostate cancer, lung cancer, breast cancer, or myeloma.

10. An anti-tumor drug, characterized in that: It comprises the β-SF5-ketone compound according to any one of claims 1 to 3, and a pharmaceutically acceptable adjuvant thereof.

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