Allyl pentafluorosulfenyl compound as well as preparation method and application thereof

Abstract

The invention discloses an allyl pentafluorosulfenyl compound as well as a preparation method and application thereof, and belongs to the technical field of organic synthesis. The structural formula of the allyl pentafluorosulfenyl compound is as follows: # imgabs0 #. The preparation method comprises the following steps: by taking an allyl compound and a pentafluorothio source as raw materials, carrying out an allylpentafluorothio reaction in a solvent under the induction of visible light to obtain the allylpentafluorothio compound by a one-step method, so that the reaction time is extremely short, the conversion of a substrate can be completed within only 15 seconds, the reaction conditions are mild, and the yield is high. The reaction can be completed under sunlight, and the allyl pentafluorosulfenyl compound derivative drug molecule has biological activity and shows a certain anticancer effect.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to an allyl pentafluorosulfur compound and a preparation method and application thereof. Background Art

[0002] 2-Pentafluorosulfur compounds have attracted extensive attention in the past few decades due to their unique properties such as high lipophilicity, high hydrolytic stability, strong polarity, high electrophilicity and low rotation barrier.

[0003] Contains SF 5 Some applications of molecules have begun to appear in the fields of materials science, drug design, and crop protection. For example, the research group of Stephen W. Fesik reported that SF 5 The group of Santiago Vazquez synthesized a soluble epoxide hydrolase inhibitor with pentafluorosulfur substitution in 2020 and evaluated its anticancer activity. Its IC value for human sEH was 50 The data showed that the pentafluorosulfur compound was an effective inhibitor of sEH in the human body. Fabrizio Pertusati's research group reported that the SF 5 The Enoborsam molecule has an IC of 50 The pentafluorosulfur compounds are only 1 / 4 of the pentafluoroethyl molecules, and the antibody activity is significantly enhanced, which significantly improves the anti-cancer activity of the drug. Pentafluorosulfur compounds also have excellent performance in the field of crop protection in agriculture, such as when CF in the herbicide trifluralin 3 By SF 5 When it is substituted, the herbicidal activity of trifluralin can be enhanced by 5 times. Therefore, it is very meaningful to develop efficient and practical synthetic methods to construct functional pentafluorosulfur compounds.

[0004] In the prior art, allyl compounds are used as active compounds in the development of anti-tumor drugs, but the biological activity of a single allyl compound is poor. Summary of the invention

[0005] The present invention provides an allyl pentafluorosulfur compound and a preparation method and application thereof. With an allyl compound as a skeleton, a functional allyl pentafluorosulfur compound is constructed. Based on the good fat solubility of pentafluorosulfur and the oxidizability of allyl in the body, the compound has good biological activity relative to a single allyl compound, shows significant anti-tumor activity, and is expected to develop new drugs.

[0006] The present invention solves the above technical problems through the following technical solutions.

[0007] The first object of the present invention is to provide an allyl pentafluorosulfur compound, the allyl pentafluorosulfur compound having the following structural formula: ; Wherein, R is selected from -PO 3 R 1 、-SO 2 R 2 , -CO 2 R 3 or -CON(CH 3 )nR 4 , halogen, boric acid pinacol ester or cyano; Among them, R 1 An alkyl group selected from C1 to C3; R 2 Selected from phenyl; R 3 A C1-C3 alkyl group, a phenyl group, a phenyl group containing a substituent, , , , , , , or ; The substituent of phenyl group is selected from cyano group, trifluoromethyl group, ester group, -SO 2 CH 3 , C1~C3 alkyl or ;in," ” is the connection site; R 4 The group is selected from phenyl or phenyl containing a substituent, the substituent of the phenyl is selected from halogen; and n is 1-3.

[0008] Further, the allyl pentafluorosulfur compound is selected from one of the following structural formulas; ; Among them, R 5 Selected from H, CF 3 , CN or CO 2 Me.

[0009] Provided is an allyl pentafluorosulfonyl compound, which uses an allyl compound as a skeleton to construct a functional allyl pentafluorosulfonyl compound. Based on the good lipid solubility of the pentafluorosulfonyl group and the oxidizability of the allyl group in the body, the allyl pentafluorosulfonyl compound has good biological activity relative to a single allyl compound, shows significant anti-tumor activity, and is expected to be developed into a new drug.

[0010] The second object of the present invention is to provide a method for preparing the above-mentioned allyl pentafluorosulfur compound, comprising the following steps: Using allyl compounds and pentafluorosulfur sources as raw materials, an allyl pentafluorosulfurization reaction is carried out in a solvent under the induction of visible light at room temperature to obtain an allyl pentafluorosulfur compound in one step. The synthetic route is as follows: .

[0011] It should be noted that the present invention forms a novel allyl pentafluorosulfur compound by combining an allyl reagent with a pentafluorosulfur reagent through a photoinduced free radical process, wherein R' is selected from sulfone, halogen, ester group or phospholipid group, wherein the sulfone can be benzenesulfonyl, p-methylbenzenesulfonyl, p-trifluoromethylbenzenesulfonyl, methylsulfonyl or trifluoromethylsulfonyl. In a preferred embodiment, R' is selected from benzenesulfonyl.

[0012] The present invention uses SF 5 Cl is used as a pentafluorosulfur source, and an allyl compound is used as a free radical scavenger. The two are subjected to free radical addition and leaving group leaving processes to form a target allyl pentafluorosulfur compound. The method can form an allyl pentafluorosulfur compound in one step, and does not require the pre-synthesis of a pentafluorosulfur compound precursor. More specifically, the present invention uses an allyl compound as a substrate and SF 5 Cl is the pentafluorosulfur source, and the photoinduced allyl compound reacts with SF 5 Allyl pentafluorosulfurization of Cl, SF 5 Cl is homogenously cleaved under sunlight to form SF 5 • and Cl•, SF 5 • Rapidly captured by the allyl group to form a new carbon radical intermediate, under the induction of the carbon radical intermediate, the leaving group leaves to form the target allyl pentafluorosulfur compound and the leaving group radical, while the leaving group radical continues to react with SF 5 The process of XAT chlorination of Cl produces SF 5 •, achieved the synthesis of a series of allyl pentafluorosulfur compounds. The reaction mechanism is as follows: .

[0013] It should be noted that R' uses -SO 2 Ph, in the allyl compound, R is selected from -CO 2 R 3 , a method for synthesizing allyl sulfone compounds, comprising the following steps: In a 25mL round-bottom flask equipped with a magnetic stirring bar, add 1.0 equivalents, 3 mmol of an alcohol compound and dissolve it in 4mL of dichloromethane. Subsequently, add 1.4 equivalents, 1.0 mL of triethylamine at room temperature, stir for 15 minutes and cool to 0°C to form a reaction system. Dissolve 1.1 equivalents, 0.8 g of 2-((phenylsulfonyl)methyl)acryloyl chloride in 3.5mL of dichloromethane and slowly add it dropwise to the above reaction system at low temperature. Monitor the reaction process by thin layer chromatography. After the reaction is completed, quench it with water, extract it with dichloromethane, wash it with water, wash it with saturated sodium chloride, dry it, filter it, concentrate it and pass it through a column. The reaction route is as follows: .

[0014] In a specific embodiment, the molar ratio of the allyl compound to the pentafluorosulfur source is 0.1:0.1-0.15.

[0015] In a specific embodiment, the wavelength of the visible light is 380 nm to 760 nm.

[0016] In a specific embodiment, the light induction time is 1 s to 15 s.

[0017] In a specific embodiment, the solvent is acetonitrile or ethyl acetate.

[0018] In a specific embodiment, the pentafluorosulfur source is a hexane solution of sulfur chloride pentafluorosulfur, and the concentration of sulfur chloride pentafluorosulfur is 0.2M to 0.5M.

[0019] The third object of the present invention is to provide the use of allyl pentafluorosulfur compound in the preparation of anti-tumor drugs.

[0020] Compared with the prior art, the present invention has the following beneficial effects: The invention provides an allyl pentafluorosulfonyl compound, which has good biological activity relative to single allyl compounds based on the good fat solubility of the pentafluorosulfonyl group and the oxidizability of the allyl group in the body, and is proved to have good biological activity in cell experiments, and is expected to be used to develop new drugs.

[0021] The present invention also provides a method for preparing an allyl pentafluorosulfur compound, comprising the following steps: photoinducing an allyl compound and SF 5 The allylic pentafluorosulfurization reaction of Cl has the characteristic that the leaving group is easily removed in the free radical reaction system, among which SF 5 Cl is homogenously cleaved under sunlight to form SF 5 • and Cl•, SF 5• Rapidly captured by the allyl group to form a new carbon radical intermediate, under the induction of the carbon radical intermediate, the leaving group leaves to form the target allyl pentafluorosulfur compound and the leaving group radical, while the leaving group radical continues to react with SF 5 The process of XAT chlorination of Cl produces SF 5 •, achieved the synthesis of a series of allyl pentafluorosulfur compounds. The reaction has the following advantages: (1) The chemical selectivity of the reaction is good, effectively inhibiting the formation of chlorinated products; (2) The reaction time is extremely short, and the conversion of the substrate is completed within only 15 seconds; (3) The reaction conditions are mild and the reaction can be completed under sunlight. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is the H NMR spectrum of the compound in Example 4 of the present invention.

[0023] Figure 2 It is the NMR carbon spectrum of the compound in Example 4 of the present invention.

[0024] Figure 3 The inhibitory effect of Example 18 of the present invention on lung adenocarcinoma is shown in FIG. Figure 3 Figure a is a representative gross image of the tumors removed from mice bearing lung adenocarcinoma tumors after different treatments, Figure b is a graph of the tumor growth curves of mice bearing lung adenocarcinoma tumors after three different treatments, and Figure c is a graph of the body weights of mice bearing lung adenocarcinoma tumors after three different treatments. DETAILED DESCRIPTION

[0025] In order to enable those skilled in the art to better understand the technical solution of the present invention and implement it, the present invention is further described below in conjunction with specific examples, but the examples are not intended to limit the present invention. The following test methods and detection methods, unless otherwise specified, are conventional methods; the reagents and raw materials, unless otherwise specified, are commercially available.

[0026] The following is further described by specific examples. Example 1 The synthesis method of 3-(trifluoromethyl)phenyl-2-((pentafluorothio)methyl)acrylate comprises the following steps: Under nitrogen atmosphere, add 185.5 mg of 3-(trifluoromethyl)phenyl-2-((phenylsulfonyl)methyl)acrylate and 5.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 2.5 mL of SF 5 Cl hexane solution, SF 5The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 seconds. After the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain the target product 3-(trifluoromethyl)phenyl-2-((pentafluorothio)methyl)acrylate, a colorless liquid with a yield of 71%. The structural formula is: .

[0027] 1 H NMR (600 MHz, CDCl 3 ) δ 7.55 (d, J = 4.8 Hz, 2H), 7.43 (s, 1H), 7.36(d, J = 3.0 Hz, 1H), 6.87 (s, 1H), 6.26 (s, 1H), 4.67 (p, J = 7.1 Hz, 2H). 13 C NMR (151 MHz, CDCl 3 ) δ 163.1, 150.6, 136.8, 132.4 (q, J = 33.2 Hz), 131.3, 130.3,125.1, 123.6 (q, J = 272.4 Hz), 123.3 (d, J = 3.6 Hz), 118.9 (d, J = 3.6 Hz), 77.4,77.1, 76.9, 71.0 (p, J = 16.4 Hz). 19 F NMR (565 MHz, CDCl 3 ) δ 86.12 – 79.44 (m,1F), 64.25 (d, J = 145.1 Hz, 4F), -62.73 (s, 3F). Example 2 The synthesis method of diethyl-3-pentafluorosulfonyl-propylene phosphate comprises the following steps: Under nitrogen atmosphere, add 190.8 mg of diethyl-3-benzenesulfonyl-propylene phosphate and 6.0 mL of ethyl acetate to a capped vial equipped with a magnetic rod, cover the vial with a capping machine, transfer out of the glove box, and inject 3.0 mL of SF 5 Cl hexane solution, SF 5The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 s; after the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain diethyl-3-pentafluorosulfonyl-propylene phosphate as a colorless liquid with a yield of 79%. The structural formula is: .

[0028] 1 H NMR (600 MHz, CDCl3) δ 6.55 (d, J = 20.8 Hz, 1H), 6.29 (d, J = 44.3Hz, 1H), 4.52 – 4.37 (m, 2H), 4.23 – 4.04 (m, 4H), 1.34 (t, J = 6.2 Hz, 6H). 13 CNMR (151 MHz, CDCl3) δ 140.1, 130.9 (d, J = 192.0 Hz), 71.2 – 70.9 (m), 62.6(d, J = 5.4 Hz), 16.3 (d, J = 5.6 Hz). 19 F NMR (565 MHz, CDCl3) δ 82.48 – 80.98 (m,1F), 65.43 (d, J = 145.7 Hz, 4F). Example 3 The synthesis method of phenyl 2-((pentafluorosulfonyl)methyl)acrylate comprises the following steps: Under nitrogen atmosphere, add 90.0 mg of phenyl 2-((phenylsulfonyl)methyl)acrylate compound and 3.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 1.5 mL of SF 5 Cl hexane solution, SF 5 The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 seconds; after the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain phenyl 2-((pentafluorosulfonyl)methyl)acrylate as a white solid with a yield of 87%. The structural formula is: .

[0029] 1H NMR (600 MHz, CDCl 3 ) δ 7.41 (d, J = 7.2 Hz, 2H), 7.28 (d, J = 6.7 Hz,1H), 7.14 (d, J = 7.4 Hz, 2H), 6.85 (s, 1H), 6.22 (s, 1H), 4.88 – 4.58 (m, 2H). 13 C NMR (151 MHz, CDCl 3 ) δ 163.5, 150.6, 136.2, 131.3, 129.7, 126.4, 121.4,71.3 – 70.9 (m). 19 F NMR (565 MHz, CDCl 3 ) δ 82.47 – 81.02 (m, 1F), 64.24 (dt, J =145.0, 6.1 Hz, 4F). Example 4 The synthesis method of 4-(trifluoromethyl)phenyl-2-((pentafluorosulfonyl)methyl)acrylate comprises the following steps: Under nitrogen atmosphere, add 185.5 mg of 4-(trifluoromethyl)phenyl-2-((phenylsulfonyl)methyl)acrylate and 5.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 2.5 mL of SF 5 Cl hexane solution, SF 5 The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 seconds. After the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain 4-(trifluoromethyl)phenyl-2-((pentafluorosulfonyl)methyl)acrylate as a colorless liquid with a yield of 75%. The H NMR spectrum was as follows Figure 1 As shown in the NMR carbon spectrum Figure 2 The structural formula is: .

[0030] 1 H NMR (600 MHz, CDCl 3 ) 1 H NMR (600 MHz, CDCl 3 ) δ 7.69 (d, J = 8.3 Hz,2H), 7.28 (d,J = 8.3 Hz, 2H), 6.87 (s, 1H), 6.27 (s, 1H), 4.67 (p, J = 7.0 Hz,2H). 13 C NMR (151 MHz, CDCl 3 ) δ 163.0, 153., 136.9, 128.8 (q, J = 32.7 Hz), 127.1(d, J = 3.4 Hz), 123.9 (dd, J = 545.1, 272.9 Hz), 122.1, 70.9 (p, J = 16.4 Hz). 19 FNMR (565 MHz, CDCl 3 ) δ 83.69 – 78.14 (m, 1F), 64.23 (dt, J = 146.7, 6.9 Hz, 4F), -62.35 (s, 3F). Example 5 The synthesis method of 4-cyanophenyl-2-((pentafluorosulfonyl)methyl)acrylate comprises the following steps: Under nitrogen atmosphere, add 163.5 mg of 4-cyanophenyl-2-((phenylsulfonyl)methyl)acrylate and 5.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 2.5 mL of SF 5 Cl hexane solution, SF 5 The concentration of Cl was 0.3M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 seconds; after the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain 4-cyanophenyl-2-((pentafluorosulfonyl)methyl)acrylate as a white solid with a yield of 87%. The structural formula is: .

[0031] 1 H NMR (600 MHz, CDCl 3 ) δ 7.73 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 8.6 Hz,2H), 6.87 (s, 1H), 6.29 (s, 1H), 4.66 (p, J = 7.1 Hz, 2H).13 C NMR (151 MHz, CDCl 3 ) δ 162.7, 153.8, 137.2, 134.0, 131.1, 122.7, 118.2, 110.6, 71.1 – 70.6(m). 19 F NMR (565 MHz, CDCl 3 ) δ 82.57 – 80.34 (m, 1F), 64.28 (d, J = 145.2 Hz,4F). Example 6 The synthesis method of methyl 4-((2-((pentafluorosulfonyl)methyl)acryloyl)oxy)benzoic acid comprises the following steps: Under nitrogen atmosphere, add 144.4 mg of methyl 4-((2-((phenylsulfonylmethyl)acryloyl)oxy)benzoic acid and 4.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 2.0 mL of SF 5 Cl hexane solution, SF 5 The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 s; after the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain methyl 4-((2-((pentafluorosulfonyl)methyl)acryloyl)oxy)benzoic acid as a white solid with a yield of 97%. The structural formula is: .

[0032] 1 H NMR (600 MHz, CDCl 3 ) δ 8.10 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.6 Hz,2H), 6.86 (s, 1H), 6.25 (s, 1H), 4.67 (p, J = 6.9 Hz, 2H), 3.93 (s, 3H). 13 C NMR (151 MHz, CDCl 3 ) δ 166.3, 163.0, 154.1, 136.7, 131.4, 128.4, 121.5, 71.1 –70.7 (m), 52.4. 19 F NMR (565 MHz, CDCl 3) δ 84.90 – 79.44 (m, 1F), 64.23 (d, J =145.2 Hz, 4F). Example 7 The synthesis method of 4-(methylsulfonyl)phenyl-2-((pentafluorosulfonyl)methyl)acrylate comprises the following steps: Under nitrogen atmosphere, add 228.0 mg of 4-(methylsulfonyl)phenyl-2-((phenylsulfonyl)methyl)acrylate and 6.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 3.0 mL of SF 5 Cl hexane solution, SF 5 The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 s; after the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain the target product 4-(methylsulfonyl)phenyl-2-((pentafluorosulfonyl)methyl)acrylate as a white solid with a yield of 76%. The structural formula is: .

[0033] 1 H NMR (600 MHz, CDCl 3 ) δ 8.01 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz,2H), 6.88 (s, 1H), 6.29 (s, 1H), 4.67 (p, J = 7.0 Hz, 2H), 3.06 (s, 3H). 13 C NMR (151 MHz, CDCl 3 ) δ 162.8, 154.5, 138.6, 137.3, 131.1, 129.5, 122.7, 71.7 –70.0 (m), 44.7. 19 F NMR (565 MHz, CDCl 3 ) δ 82.51 – 81.12 (m, 1F), 63.68 (dt, J =144.1, 6.8 Hz, 4F). Example 8 N- The synthetic method of methyl-2-[(pentafluorosulfonyl)methyl]-N-phenylacrylamide comprises the following steps: Under nitrogen atmosphere, add 189.0 mg of N-methyl-2-[(phenylsulfonyl)methyl]-N-phenylacrylamide and 6.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 3.0 mL of SF 5 Cl hexane solution, SF 5 The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 seconds. After the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain the target product. N -Methyl-2-[(pentafluorosulfonyl)methyl]-N-phenylacrylamide, white solid, yield 66%. The structural formula is: .

[0034] 1 H NMR (600 MHz, CDCl 3 ) δ 7.42 – 7.36 (m, 2H), 7.33 – 7.28 (m, 1H),7.21 (d, J = 7.7 Hz, 2H), 5.62 (s, 1H), 5.40 (s, 1H), 4.57 – 4.46 (m, 2H), 3.41(s, 3H). 13 C NMR (151 MHz, CDCl 3 ) δ 166.8, 144.3, 134.8, 131.0., 129.8, 127.7,126.6, 77.4, 77.2, 76.9, 74.20 – 73.51 (m), 39.2. 19 F NMR (565 MHz, CDCl 3 ) δ83.38 – 81.88 (m, 1F), 65.76 (dt, J = 145.2, 7.1 Hz, 4F). Example 9 N -4-bromo-N-methyl-2-[(pentafluorosulfonyl)methyl]acrylamide synthesis method, comprising the following steps: Under nitrogen atmosphere, add 196.5 mg of N-4-bromo-N-methyl-2-[(phenylsulfonyl)methyl]acrylamide and 6.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 3.0 mL of SF 5 Cl hexane solution, SF 5The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 s. After the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain the target product. N -4-Bromo-N-methyl-2-[(pentafluorosulfonyl)methyl]acrylamide, white solid, yield 54%. The structural formula is: .

[0035] 1 H NMR (600 MHz, CDCl 3 ) δ 7.52 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.5 Hz,2H), 5.67 (s, 1H), 5.40 (s, 1H), 4.57 (p, J = 7.5 Hz, 2H), 3.38 (s, 3H). 13 C NMR (151 MHz, CDCl 3 ) δ 166.8, 143.3, 134.5, 133.0, 130.8, 128.2, 121.3, 75.5 –71.8 (m), 39.2. 19 F NMR (565 MHz, CDCl 3 ) δ 84.51 – 80.14 (m, 1F), 65.07 (d, J =144.0 Hz, 4F). Example 10 The synthesis method of 2-((pentafluorothio)methyl)benzenesulfonyl acrylic acid comprises the following steps: Under nitrogen atmosphere, add 258.4 mg of 2-((phenylsulfonyl)methyl)phenylsulfonyl acrylic acid and 8.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 4.0 mL of SF 5 Cl hexane solution, SF 5 The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 s; after the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain the target product 2-((pentafluorothio)methyl)benzenesulfonylacrylic acid as a white solid with a yield of 89%. The structural formula is: .

[0036] 1 H NMR (600 MHz, CDCl 3 ) δ 7.90 (d, J = 7.7 Hz, 2H), 7.73-7.62 (m, 1H), 7.62-7.51 (m, 2H), 6.86 (s, 1H), 6.36 (s, 1H), 4.63 – 4.45 (m, 2H). 13 C NMR (151 MHz, CDCl 3 ) δ 142.6, 138.2, 134.7, 134.4, 129.6, 128.8, 67.9 – 67.1 (m). 19 F NMR (565 MHz, CDCl 3 ) δ 81.01 – 79.18 (m, 1F), 65.94 (dd, J = 152.5, 6.1 Hz,4F). Embodiment 11 The synthesis method of 2-((pentafluorothio)methyl)benzyl acrylate comprises the following steps: Under nitrogen atmosphere, add 190.2 mg of 2-((phenylsulfonyl)methyl)benzyl acrylate and 6.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial with a capping machine, transfer out of the glove box, and inject 3.0 mL of SF 5 Cl hexane solution, SF 5 The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 s; after the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain the target product 2-((pentafluorothio)methyl)benzyl acrylate as a colorless liquid with a yield of 91%. The structural formula is: .

[0037] 1 H NMR (600 MHz, CDCl 3 ) δ 7.45 – 7.30 (m, 4H), 6.66 (s, 1H), 6.06 (s,1H), 5.27 (s, 2H), 4.82 – 4.52 (m, 2H). 13 C NMR (151 MHz, CDCl 3) δ 164.8,135.5, 135.0, 128.8, 128.6, 128.4, 72.3 – 69.6 (m), 67.6, 29.8, 29.9. 19 F NMR (565 MHz, CDCl 3 ) δ 83.01 – 80.64 (m, 1F), 64.13 (dt, J = 145.1, 7.2 Hz, 4F). Example 12 The synthesis method of allyl pentafluorosulfur compound comprises the following steps: Under nitrogen atmosphere, add 103.33 mg of 3-phenylpropyl 2-((phenylsulfonyl)methyl)acrylate and 3.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 1.5 mL of SF 5 Cl hexane solution, SF 5 The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 seconds. After the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain the target product 3-phenylpropyl 2-((pentafluorothio)methyl)acrylate, a colorless liquid with a yield of 81%. The structural formula is: .

[0038] 1 H NMR (600 MHz, CDCl 3 ) δ 7.34 – 7.25 (m, 2H), 7.23 – 7.12 (m, 3H), 6.60 (s, 1H), 6.02 (s, 1H), 4.60 – 4.50 (m, 2H), 4.35 – 4.15 (m, 2H), 2.72 –2.56 (m, 2H), 1.79 – 1.67 (m, 4H). 13 C NMR (151 MHz, CDCl 3 ) δ 164.9, 142.1,134.5, 132.3, 128.6, 128.5, 126.1, 71.5 – 70.9 (m), 65.7, 35.6, 28.3, 27.7. 19 FNMR (565 MHz, CDCl 3 ) δ 82.81 – 81.14 (m, 1F), 64.12 (d, J= 145.0 Hz, 4F). Example 13 The synthesis method of 7-hydroxycoumarin-2-((pentafluorothio)methyl)acrylate comprises the following steps: Under nitrogen atmosphere, add 222.3 mg of 7-hydroxycoumarin-2-((phenylsulfonyl)methyl)acrylate and 6.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 3.0 mL of SF 5 Cl hexane solution, SF 5 The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 seconds. After the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain the target product 7-hydroxycoumarin-2-((pentafluorothio)methyl)acrylate as a white solid with a yield of 89%. The structural formula is: .

[0039] 1 H NMR (600 MHz, CDCl 3 ) δ 7.70 (d, J = 9.4 Hz, 1H), 7.51 (d, J = 8.5 Hz,1H), 7.15 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.87 (s, 1H), 6.49 – 6.35 (m, 1H), 6.28 (s, 1H), 4.74 – 4.61 (m, 2H). 13 C NMR (151 MHz, CDCl 3 ) δ 162.9, 160.2,154.8, 152.9, 142.9, 137.2, 131.1, 128.9, 118.2, 117.2, 116.5, 110.4, 71.6 –70.4 (m). 19 F NMR (565 MHz, CDCl 3 ) δ 82.38 – 80.90 (m, 1F), 64.29 (dt, J = 145.1,6.0 Hz, 4F). Embodiment 14 The synthesis method of tyrosine methyl ester-2-((pentafluorosulfenyl)methyl)acrylate comprises the following steps: Under nitrogen atmosphere, add 322.2 mg of tyrosine methyl ester-2-((phenylsulfonyl)methyl)acrylate and 6.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 3.0 mL of SF 5 Cl hexane solution, SF 5 The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 seconds. After the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain the target product, tyrosine methyl ester-2-((pentafluorothio)methyl)acrylate, as a white solid with a yield of 82%. The structural formula is: .

[0040] 1 H NMR (600 MHz, CDCl 3 ) δ 7.39 – 7.30 (m, 5H), 7.13 (d, J = 8.4 Hz, 2H),7.05 (d, J = 8.5 Hz, 2H), 6.83 (s, 1H), 6.21 (s, 1H), 5.23 (d, J = 7.7 Hz, 1H), 5.10 (m, 2H), 4.73 – 4.60 (m, 3H), 3.73 (s, 3H), 3.13 (ddd, J = 40.9, 13.9, 5.7 Hz, 2H). 13 C NMR (151 MHz, CDCl 3 ) δ 171.9, 163.4, 155.7, 149.7, 136.6, 136.3,134.0, 131.7, 130.5, 128.7, 128.3, 128.3, 121.6, 71.8 – 70.1 (m), 67.2, 54.9,52.5, 37.8. 19 F NMR (565 MHz, CDCl 3 ) δ 85.77 – 79.00 (m, 1F), 64.24 (dt, J =145.1 Hz, 6.1 Hz, 4F). Embodiment 15 The synthesis method of 4-hydroxycoumarin-2-((pentafluorothio)methyl)acrylate comprises the following steps: Under nitrogen atmosphere, add 222.3 mg of 4-hydroxycoumarin-2-((phenylsulfonyl)methyl)acrylate and 6.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 3.0 mL of SF 5 Cl hexane solution, SF 5 The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 s; after the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain the target product 4-hydroxycoumarin-2-((pentafluorothio)methyl)acrylate as a white solid with a yield of 79%. The structural formula is: .

[0041] 1 H NMR (600 MHz, CDCl 3 ) δ 7.71 (d, J = 9.5 Hz, 1H), 7.52 (dd, J = 8.4, 2.2Hz, 1H), 7.17 (d, J = 4.0 Hz, 1H), 7.10 (dd, J = 8.4, 3.5 Hz, 1H), 6.88 (s, 1H), 6.47 – 6.36 (m, 1H), 6.28 (s, 1H), 4.67 (p, J = 7.0 Hz, 2H). 13 C NMR (151 MHz, CDCl 3 ) δ 162.9, 160.2, 154.8, 152.9, 142.8, 137.1, 131.2, 128.9, 118.2,117.2, 116.5, 110.4, 71.5 – 70.2 (m). 19 F NMR (565 MHz, CDCl 3 ) δ 83.06 – 80.50(m, 1F), 64.31 (d, J = 145.1 Hz, 4F). Example 16 The synthesis method of RU 58841-2-((pentafluorothio)methyl)acrylate comprises the following steps: Under nitrogen atmosphere, add 300.1 mg RU 58841-2-((phenylsulfonyl)methyl)acrylate and 6.0 mL acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 3.0 mL SF 5 Cl hexane solution, SF 5 The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 seconds. After the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain the target product RU 58841-2-((pentafluorothio)methyl)acrylate as a white solid with a yield of 89%. The structural formula is: .

[0042] 1 H NMR (600 MHz, CDCl 3 ) δ 8.13 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.89(d, J = 8.4 Hz, 1H), 6.61 (s, 1H), 6.04 (s, 1H), 4.59 – 4.52 (m, 2H), 4.28 (s, 2H), 3.39 (s, 2H), 1.79 (s, 4H), 1.51 (s, 6H). 13 C NMR (151 MHz, CDCl 3 ) δ174.7, 164.8, 153.0, 136.7, 135.3, 135.0, 133.6 (q, J = 33.1 Hz), 131.9, 128.0,123.1, 123.0,122.1 (q, J = 269.4 Hz), 115.1, 108.3, 72.4 – 69.9 (m), 64.9,62.0, 40.0, 26.3, 26.1, 23.5. 19 F NMR (565 MHz, CDCl 3 ) δ 82.73-81.60. (m, 1F),63.99 (d, J = 145.0 Hz, 4F), -62.06 (s, 3F). Embodiment 17 The synthesis method of epiandrosterone-2-((pentafluorosulfenyl)methyl)acrylate comprises the following steps: Under nitrogen atmosphere, add 299.4 mg of epiandrosterone-2-((phenylsulfonyl)methyl)acrylate and 6.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 3.0 mL of SF 5 Cl hexane solution, SF 5 The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 s. After the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain the target product, epiandrosterone-2-((pentafluorothio)methyl)acrylate, as a white solid with a yield of 83%. The structural formula is: .

[0043] 1 H NMR (600 MHz, CDCl 3 ) δ 6.59 (s, 1H), 5.99 (s, 1H), 5.00 – 4.75 (m,1H), 4.65 – 4.45 (m, 2H), 2.44 (dd, J = 19.3, 8.8 Hz, 1H), 2.13 – 2.02 (m, 1H), 1.98 – 1.85 (m, 2H), 1.79 (t, J = 15.0 Hz, 3H), 1.71 – 1.62 (m, 2H), 1.62 –1.55 (m, 1H), 1.52 – 1.40 (m, 2H), 1.39 – 1.19 (m, 7H), 1.13 – 0.94 (m, 2H), 0.87 (d, J = 4.8 Hz, 6H), 0.79 – 0.70 (m, 1H). 13 C NMR (151 MHz, CDCl 3 ) δ 221.1,164.3, 134.3, 132.5, 75.2, 71.6 – 70.9 (m), 54.5, 51.5, 47.9, 44.8, 36.8,35.9, 35.8, 35.2, 33.8, 31.7, 30.9, 28.4, 27.3, 21.9, 20.6, 13.9, 12.3. 19 F NMR (565 MHz, CDCl 3 ) δ 82.92 – 80.80 (m, 1F), 64.00 (d,J = 145.2 Hz, 4F). Embodiment 18 The synthesis method of testosterone-2-((pentafluorothio)methyl)acrylate comprises the following steps: Under nitrogen atmosphere, add 300.2 mg of testosterone-2-((phenylsulfonyl)methyl)acrylate and 6.0 mL of acetonitrile to a capped vial equipped with a magnetic rod, cover the vial and press it tightly with a capping machine, transfer out of the glove box, and inject 3.0 mL of SF 5 Cl hexane solution, SF 5 The concentration of Cl was 0.3 M, and the reaction bottle was placed under sunlight and stirred vigorously for 15 s; after the reaction was completed, the gas in the capped vial was carefully discharged with a needle, the solvent was removed in vacuo, and the residue was quickly purified by silica gel column chromatography to obtain the target product testosterone-2-((pentafluorothio)methyl)acrylate as a white solid with a yield of 41%. The structural formula is: .

[0044] 1 H NMR (600 MHz, CDCl 3 ) δ 6.61 (s, 1H), 6.02 (s, 1H), 4.74 (t, J = 8.5Hz, 1H), 4.64 – 4.49 (m, 2H), 3.27 (d, J = 15.0 Hz, 1H), 2.63 – 2.49 (m, 2H), 2.30 – 2.14 (m, 2H), 2.09 – 1.35 (m, 10H), 1.30 – 1.19 (m, 5H), 1.14 – 0.96(m, 3H), 0.89 (s, 3H). 13 C NMR (151 MHz, CDCl 3 ) δ 190.8, 164.8, 134.8, 127.6,83.9, 71.6 – 70.7 (m), 54.0, 50.3, 42.9, 41.5, 36.7, 35.1, 34.6, 34.1, 30.8,29.0, 27.5, 23.6, 20.8, 17.9, 12.2. 19 F NMR (565 MHz, CDCl 3 ) δ 82.12 (m, 1F),64.16 (d, J = 145.1 Hz, 4F). In order to verify the key parameters of pentafluorosulfonamide modified compounds in IC 50 The present invention has biological activity with non-fluorinated motifs, and has a 5 To test the anticancer activity of the molecule, the propyl pentafluorosulfur compound prepared in Example 13, Example 15 to Example 18 and the corresponding non-fluorine motif compounds in Example 13, Example 15 to Example 18 were used in a systematic evaluation experiment of various cancer cell lines. The non-fluorine motif compounds in Example 13, Example 15 to Example 18 were named control group 13, control group 15, control group 16, control group 17 and control group 18.

[0045] The structural formula of the control group 13 is shown below: .

[0046] The structural formula of the control group 15 is shown below: .

[0047] The structural formula of the control group 16 is shown below: .

[0048] The structural formula of the control group 17 is shown below: .

[0049] The structural formula of the control group 18 is shown below: .

[0050] The propyl pentafluorosulfur compounds prepared in Examples 13 and 15 to 18 and the corresponding non-fluorinated motif compounds in Examples 13 and 15 to 18 were used in a variety of cancer cell lines, including the following steps: human cancer cells H820, MCF-7, PC-3, Huh-7, PANC-1 and SMMC-7721 were placed in a 5% CO 2, in a humidified incubator at 37°C, DMEM medium contained 10% fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin. H820 cells, MCF-7 cells, PC-3 cells, Huh-7 cells, PANC-1 cells and SMMC-7721 cells were seeded into 96-well plates (4000 cells / well) and treated with compounds at different concentrations of 100 μmol, 50 μmol, 20 μmol, 10 μmol, 5 μmol, 2 μmol, 1 μmol and 0 μmol for 72 h, and then 20 μL of MTT at a concentration of 5 mg / mL was added to the cell culture medium for another 4 h, and then the culture medium was discarded and the precipitate was dissolved with DMSO. The absorbance was measured at 570 nm using a microplate reader. All experiments were repeated three times independently, and IC was calculated using GraphPad Prism 8 50 Among them, H820 is a human lung adenocarcinoma cell; MCF-7 is a human breast cancer cell; PC-3 is a human prostate cancer cell; Huh-7 is a human liver cancer cell; PANC-1 is a human pancreatic cancer cell; and SMMC-7721 is a human liver cancer cell.

[0051] Table 1 IC values ​​of allyl pentafluorosulfur compounds prepared in Examples 13 and 15 to 18 50 result

[0052] In order to verify the biological activity of pentafluorosulfur modified compounds and non-fluorine motifs, the present invention is to 5 The anticancer activity of the molecule was tested in animal experiments, and the testosterone-2-((pentafluorothio)methyl)acrylate compound prepared in the representative Example 18 was selected for mouse experiments. A lung adenocarcinoma patient-derived tumor xenograft (PDX) mouse model was used to evaluate the in vivo therapeutic effect and improve clinical predictability. Corn germ oil was used as control group 1, and a fluorine-free testosterone-2 methacrylate compound was used as control group 2, for a total of three groups, with 6 mice in each group, wherein the structure of the fluorine-free testosterone-2 methacrylate compound is shown below: .

[0053] The testosterone-2-((pentafluorothio)methyl)acrylate compound prepared in Example 18, corn germ oil, and the fluorine-free testosterone-2-methacrylate compound were intraperitoneally injected at a dose of 40 mg / kg every 4 days. The tumor was removed and tested after 31 days. The results were as follows: Figure 3 shown.

[0054] Figure 3 The inhibitory effect of Example 18 of the present invention on lung adenocarcinoma is shown in FIG. Figure 3Figure a is a representative general picture of the tumor removed from mice bearing lung adenocarcinoma tumors after different treatments, Figure b is a graph of the tumor growth curves of mice bearing lung adenocarcinoma tumors after three different treatments, and Figure c is a graph of the body weights of mice bearing lung adenocarcinoma tumors after three different treatments. Figure 3 As shown, the testosterone-2-((pentafluorothio)methyl)acrylate compound prepared in Example 18 significantly reduced tumor volume, with a tumor inhibition rate of about 60%. In contrast, the experimental results of the control group of corn germ oil and the testosterone-2 methacrylate compound without fluorine were similar, and tumor growth increased rapidly. These results show that SF 5 The modifier was effective in cancer treatment. At the same time, during the administration period, the weight of the mice remained the same as that of the control group, indicating that the drug had low toxicity. Therefore, compared with the precursor, the pentafluorosulfonyl-modified derivative has a high therapeutic effect in animal experiments, and its therapeutic effect at the cellular level is also obvious.

[0055] Although the preferred embodiments of the present invention have been described, those skilled in the art may make other changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0056] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. An allyl pentafluorosulfur compound, characterized in that: The structural formula of the allyl pentafluorosulfur compound is as follows: ； Wherein, R is selected from -PO3R1, -SO2R2, -CO2R3 or -CON(CH3) n R4, halogen, boric acid pinacol ester or cyano; Wherein, R1 is selected from C1~C3 alkyl; R2 is selected from phenyl; R3 is selected from C1~C3 alkyl, phenyl, phenyl containing a substituent, , , , , , , or ; The substituent of phenyl group is selected from cyano group, trifluoromethyl group, ester group, -SO2CH3, C1~C3 alkyl or ;in," ” is the connection site; R4 is selected from phenyl or phenyl containing a substituent, and the substituent of the phenyl is selected from halogen; n is 1-3.

2. The allyl pentafluorosulfur compound according to claim 1, characterized in that: The allyl pentafluorosulfur compound is selected from one of the following structural formulas; ； Wherein, R5 is selected from H, -CF3, -CN or -CO2Me.

3. A method for preparing the allyl pentafluorosulfur compound according to claim 1 or claim 2, characterized in that: The following steps are involved: With an allyl compound and a pentafluorosulfenyl source as raw materials, an allyl pentafluorosulfenylation reaction is carried out in a solvent at room temperature under the induction of visible light to obtain an allyl pentafluorosulfenyl compound in one step.

4. The method for synthesizing an allyl pentafluorosulfur compound according to claim 3, characterized in that: The molar ratio of the allyl compound to the pentafluorosulfur source is 0.1:0.1-0.

15.

5. The method for synthesizing an allyl pentafluorosulfur compound according to claim 3, characterized in that: The wavelength of the visible light is 380 nm to 760 nm.

6. The method for synthesizing an allyl pentafluorosulfur compound according to claim 3, characterized in that: The light induction time is 1 s to 15 s.

7. The method for synthesizing an allyl pentafluorosulfur compound according to claim 3, characterized in that: The solvent is acetonitrile or ethyl acetate.

8. The method for synthesizing an allyl pentafluorosulfur compound according to claim 3, characterized in that: The pentafluorosulfur source is a hexane solution of pentafluorosulfur chloride, and the concentration of pentafluorosulfur chloride is 0.2M-0.5M.

9. Use of the allyl pentafluorosulfur compound according to claim 1 or claim 2 in the preparation of anti-tumor drugs.

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