An allyl pentafluorosulfanyl compound, its preparation method and application

Abstract

The present invention discloses an allyl pentafluorosulfanyl compound, a preparation method thereof and an application thereof, belonging to the technical field of organic synthesis. The structural formula of the allyl pentafluorosulfanyl compound is as follows:. The preparation method comprises the following steps: using an allyl compound and a pentafluorosulfanyl source as raw materials, carrying out an allyl pentafluorosulfanylation reaction under visible light induction in a solvent, and obtaining the allyl pentafluorosulfanyl compound in one step. The reaction time is extremely short, and the conversion of the substrate can be completed within only 15 seconds, and the reaction conditions are mild, and the reaction can be completed under sunlight. The allyl pentafluorosulfanyl compound-derived drug molecules have biological activities and exhibit certain anti-cancer effects.

Description

Technical Field

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

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

[0003] Some applications of SF5-containing molecules have begun to appear in the fields of materials science, drug design, and crop protection. For example, the Stephen W. Fesik research group in the prior art reported the synthesis of MYC protein inhibitors containing the SF5 group and characterized and studied their structures and properties. The Santiago Vazquez research group synthesized soluble epoxide hydrolase inhibitors substituted with pentafluorosulfanyl groups in 2020 and evaluated their anticancer activities. The IC 50 for its inhibition of human sEH was 35.9. This data indicates that this pentafluorosulfanyl compound is an effective inhibitor of human sEH; the Fabrizio Pertusati research group reported the Enoborsam molecule containing the SF5 group. The IC 50 of this molecule is only 1 / 4 of that of the pentafluoroethyl-containing molecule, and the antibody activity is significantly enhanced, resulting in a significant increase in the anticancer activity of this drug. Pentafluorosulfanyl compounds also have excellent performance in the field of crop protection in agriculture. For example, when CF3 in the herbicide trifluralin is replaced by SF5, the herbicidal activity of trifluralin can be enhanced by 5 times. Therefore, it is very meaningful to develop efficient and practical synthesis methods to construct functional pentafluorosulfanyl compounds.

[0004] In the prior art, allyl compounds are used as active compounds for the development of antitumor drugs, but the biological activity of single allyl compounds is poor. Summary of the Invention

[0005] The present invention provides an allyl pentafluorosulfanyl compound, a preparation method thereof, and an application thereof. Based on the allyl compound as the backbone, a functional allyl pentafluorosulfanyl compound is constructed. Due to the good lipophilicity of pentafluorosulfanyl and the oxidizability of allyl in vivo, it has good biological activity compared with single allyl compounds, shows significant antitumor 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 pentafluorosulfanyl compound, and the structural formula of the allyl pentafluorosulfanyl compound is as follows:

[0008] ;

[0009] Wherein, R is selected from -PO3R1, -SO2R2, -CO2R3 or -CON(CH3)nR4, halogen, pinacol borate or cyano;

[0010] Wherein, R1 is selected from C1-C3 alkyl;

[0011] R2 is selected from phenyl;

[0012] R3 is selected from C1-C3 alkyl, phenyl, substituted phenyl, , , , , , , or ; The substituents of phenyl are selected from cyano, trifluoromethyl, ester group, -SO2CH3, C1-C3 alkyl or ; Wherein, " " is the connection site;

[0013] R4 is selected from phenyl or substituted phenyl, and the substituents of phenyl are selected from halogen; n is 1-3.

[0014] Furthermore, the allyl pentafluorosulfanyl compound is selected from one of the following structural formulas;

[0015] ;

[0016] Wherein, R5 is selected from H, CF3, CN or CO2Me.

[0017] Provided is an allyl pentafluorosulfanyl compound, which constructs a functional allyl pentafluorosulfanyl compound based on an allyl compound as a skeleton. Due to the good liposolubility of the pentafluorosulfanyl group and the oxidizability of the allyl group in vivo, it has good biological activity relative to a single allyl compound, shows significant anti-tumor activity, and is expected to develop new drugs.

[0018] The second object of the present invention is to provide a preparation method of the above-mentioned allyl pentafluorosulfanyl compound, including the following steps:

[0019] Using an allyl compound and a pentafluorosulfanyl source as raw materials, under visible light induction in a solvent, an allyl pentafluorosulfanylation reaction is carried out at room temperature to obtain an allyl pentafluorosulfanyl compound in one step. The synthesis route is as follows:

[0020] .

[0021] It should be noted that in the present invention, a novel allyl pentafluorothio group compound is formed through a photoinduced radical process by combining an allyl reagent with a pentafluorothio group reagent, where R' is selected from sulfone, halogen, ester group, phospholipid group, etc. Among them, the sulfone can be benzenesulfonyl, p-toluenesulfonyl, p-trifluoromethylbenzenesulfonyl, methylsulfonyl or trifluoromethylsulfonyl. In a preferred embodiment, R' is selected from benzenesulfonyl.

[0022] In the present invention, SF5Cl is used as the pentafluorothio group source, and the allyl compound is used as a radical scavenger. The two form the target allyl pentafluorothio group compound through a radical addition and leaving group leaving process. This method can form the allyl pentafluorothio group compound in one step and does not require the pre-synthesis of the pentafluorothio group compound precursor. More specifically, in the present invention, an allyl compound is used as the substrate and SF5Cl is used as the pentafluorothio group source. By using a photoinduced allyl pentafluorothiolation reaction of the allyl compound and SF5Cl, SF5Cl undergoes homolytic cleavage under the irradiation of a sun lamp to form SF5• and Cl•. SF5• is 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 pentafluorothio group compound and the leaving group radical, and the leaving group radical continues to undergo the XAT chlorine extraction process with SF5Cl to generate SF5•, realizing the synthesis of a series of allyl pentafluorothio group compounds. The reaction mechanism is as follows:

[0023] 。

[0024] It should be noted that when R' is selected as -SO2Ph, in the allyl compound, R is selected from -CO2R3. The synthetic method of allyl sulfone compounds includes the following steps:

[0025] In a 25 mL round-bottom flask equipped with a magnetic stir bar, 1.0 equivalent, 3 mmol of an alcohol compound was added and dissolved in 4 mL of dichloromethane. Subsequently, 1.4 equivalents, 1.0 mL of triethylamine was added at room temperature, and after stirring for 15 min, it was cooled to 0 °C to form a reaction system. 1.1 equivalents, 0.8 g of 2-((phenylsulfonyl)methyl)acryloyl chloride was dissolved in 3.5 mL of dichloromethane and slowly added dropwise to the above reaction system at low temperature. The reaction process was monitored by thin-layer chromatography. After the reaction was completed, it was quenched with water, extracted with dichloromethane, washed with water, washed with saturated sodium chloride, dried, filtered and concentrated, and then passed through a column. The reaction route is as follows:

[0026] 。

[0027] In a specific embodiment, the molar ratio of the allyl compound to the pentafluorothio group source is 0.1:0.1 to 0.15.

[0028] In a specific embodiment, the wavelength of the visible light is 380 nm to 760 nm.

[0029] In a specific embodiment, the time of photoinduction is 1 s to 15 s.

[0030] In a specific embodiment, the solvent is acetonitrile or ethyl acetate.

[0031] In a specific embodiment, the pentafluorosulfanyl source is a hexane solution of sulfur pentafluoride chloride, and the concentration of sulfur pentafluoride chloride is 0.2 M to 0.5 M.

[0032] The third object of the present invention is to provide the use of allyl pentafluorosulfanyl compounds in the preparation of anti-tumor drugs.

[0033] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0034] The present invention provides an allyl pentafluorosulfanyl compound. Based on the good liposolubility of pentafluorosulfanyl and the oxidizability of allyl in vivo, it has good biological activity compared with a single allyl compound, and it has been proved to have good biological activity in cell experiments, and is expected to develop new drugs.

[0035] The present invention also provides a preparation method of allyl pentafluorosulfanyl compounds, which includes the following steps: a photoinduced allyl pentafluorosulfanylation reaction of an allyl compound and SF5Cl, and the characteristic that the leaving group is easily removed in a radical reaction system. Among them, SF5Cl undergoes homolysis under the irradiation of a sun lamp to form SF5• and Cl•, SF5• is quickly captured by the allyl to form a new carbon radical intermediate, and under the induction of the carbon radical intermediate, the leaving group leaves to form the target allyl pentafluorosulfanyl compound and the leaving group radical, and the leaving group radical continues to undergo the process of XAT chlorine extraction with SF5Cl to generate SF5•, realizing the synthesis of a series of allyl pentafluorosulfanyl compounds. This 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 can be completed within only 15 seconds; (3) The reaction conditions are mild, and the reaction can be completed under sunlight. Description of the Drawings

[0036] Figure 1 It is the 1H NMR spectrum of the compound in Example 4 of the present invention.

[0037] Figure 2 It is the 13C NMR spectrum of the compound in Example 4 of the present invention.

[0038] Figure 3 It is the inhibitory effect on lung adenocarcinoma in Example 18 of the present invention. Figure 3Figure a in it is a representative gross image of the excised tumor of lung adenocarcinoma tumor mice after different treatments, Figure b is a tumor growth curve graph of lung adenocarcinoma tumor mice after three different treatments, and Figure c is a body weight graph of lung adenocarcinoma tumor mice after three different treatments. Detailed implementation manners

[0039] To enable those skilled in the art to better understand and implement the technical solutions of the present invention, the present invention will be further described below in conjunction with specific embodiments. However, the specific embodiments cited do not limit the present invention. The following test methods and detection methods are all conventional methods unless otherwise specified; the reagents and raw materials are all commercially available unless otherwise specified.

[0040] The following is further illustrated by specific embodiments

[0041] Example 1

[0042] The synthesis method of 3-(trifluoromethyl)phenyl-2-((pentafluorothio)methyl)acrylate includes the following steps:

[0043] Under a 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 stir bar. Cover the bottle cap and tighten it with a crimper, then take it out of the glove box. Inject 2.5 mL of a n-hexane solution of SF5Cl with a concentration of 0.3 M into the mixture. Place the reaction flask under sunlight and stir vigorously for 15 s; after the reaction is completed, carefully discharge the gas in the capped vial with a syringe needle, remove the solvent under vacuum, and quickly purify the residue 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:

[0044] .

[0045] 1 H NMR (600 MHz, CDCl3) δ 7.55 (d, J J = 4.8 Hz, 2H), 7.43 (s, 1H), 7.36(d, J J = 3.0 Hz, 1H), 6.87 (s, 1H), 6.26 (s, 1H), 4.67 (p, J J = 7.1 Hz, 2H). 13 C NMR(151 MHz, CDCl3) 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 19F NMR (565 MHz, CDCl3) δ 86.12 – 79.44 (m, 1F), 64.25 (d, J = 145.1 Hz, 4F), -62.73 (s, 3F).

[0046] Example 2

[0047] Synthesis method of diethyl 3-(pentafluorosulfuryl)acrylate phosphate, comprising the following steps:

[0048] Under a nitrogen atmosphere, 190.8 mg of diethyl 3-(phenylsulfonyl)acrylate phosphate and 6.0 mL of ethyl acetate were added to a capped vial equipped with a magnetic stir bar. The vial was capped and crimped with a crimper, removed from the glove box, and 3.0 mL of a SF5Cl n-hexane solution with a concentration of 0.3 M was injected into the mixture. The reaction flask was placed in 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 under vacuum, and the residue was purified rapidly by silica gel column chromatography to obtain diethyl 3-(pentafluorosulfuryl)acrylate phosphate, a colorless liquid, with a yield of 79%. The structural formula is:

[0049] .

[0050] 1 1H NMR (600 MHz, CDCl3) δ 6.55 (d, J = 20.8 Hz, 1H), 6.29 (d, J = 44.3 Hz, 1H), 4.52 – 4.37 (m, 2H), 4.23 – 4.04 (m, 4H), 1.34 (t, J = 6.2 Hz, 6H). 13 13C NMR (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 19F NMR (565 MHz, CDCl3) δ 82.48 – 80.98 (m,1F), 65.43 (d, J = 145.7 Hz, 4F).

[0051] Example 3

[0052] Synthesis method of phenyl 2-((pentafluorosulfonyl)methyl)acrylate, comprising the following steps:

[0053] Under a nitrogen atmosphere, 90.0 mg of phenyl 2-((benzenesulfonyl)methyl)acrylate compound and 3.0 mL of acetonitrile were added to a capped vial equipped with a magnetic stir bar. The bottle cap was covered and tightened with a crimper, then taken out of the glove box. 1.5 mL of a n-hexane solution of SF5Cl with a concentration of 0.3 M was injected into the mixture. The reaction flask was placed in sunlight and stirred vigorously for 15 s. After the reaction was completed, the gas in the capped vial was carefully discharged with a syringe needle, and the solvent was removed under vacuum. The residue was purified rapidly by silica gel column chromatography to obtain phenyl 2-((pentafluorosulfonyl)methyl)acrylate, a white solid, with a yield of 87%. The structural formula is:

[0054] .

[0055] 1 1H NMR (600 MHz, CDCl3) 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 13C NMR (151 MHz, CDCl3) δ 163.5, 150.6, 136.2, 131.3, 129.7, 126.4, 121.4,71.3 – 70.9 (m). 19 19F NMR (565 MHz, CDCl3) δ 82.47 – 81.02 (m, 1F), 64.24 (dt, J =145.0, 6.1 Hz, 4F).

[0056] Example 4

[0057] Synthesis method of 4-(trifluoromethyl)phenyl-2-((pentafluorosulfonyl)methyl)acrylate, comprising the following steps:

[0058] Under a 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 stirrer. Cover the vial cap and tighten it with a crimper. Remove it from the glove box, inject 2.5 mL of a n-hexane solution of SF5Cl with a concentration of 0.3 M into the mixture. Place the reaction flask under sunlight and stir vigorously for 15 s. After the reaction is complete, carefully discharge the gas in the capped vial with a syringe needle, remove the solvent under vacuum, and rapidly purify the residue by silica gel column chromatography to obtain 4-(trifluoromethyl)phenyl-2-((pentafluorosulfonyl)methyl)acrylate, a colorless liquid with a yield of 75%. The 1H NMR spectrum is as follows Figure 1 shown, and the 13C NMR spectrum is as follows Figure 2 shown. The structural formula is:

[0059] .

[0060] 1 1H NMR (600 MHz, CDCl3) 1 1H NMR (600 MHz, CDCl3) δ 7.69 (d, J J = 8.3 Hz, 2H), 7.28 (d, J J = 8.3 Hz, 2H), 6.87 (s, 1H), 6.27 (s, 1H), 4.67 (p, J J = 7.0 Hz, 2H). 13 13C NMR (151 MHz, CDCl3) δ 163.0, 153., 136.9, 128.8 (q, J J = 32.7 Hz), 127.1 (d, J J = 3.4 Hz), 123.9 (dd, J J = 545.1, 272.9 Hz), 122.1, 70.9 (p, J J = 16.4 Hz). 19 19F NMR (565 MHz, CDCl3) δ 83.69 – 78.14 (m, 1F), 64.23 (dt, J J = 146.7, 6.9 Hz, 4F), -62.35 (s, 3F).

[0061] Example 5

[0062] Synthesis method of 4-cyanophenyl 2-((pentafluorosulfonyl)methyl)acrylate, comprising the following steps:

[0063] Under a 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 stir bar, cover the bottle cap and tighten it with a crimper, remove it from the glove box, inject 2.5 mL of a SF5Cl n-hexane solution with a concentration of 0.3 M into the mixture, place the reaction flask under sunlight and stir vigorously for 15 s; after the reaction is completed, carefully discharge the gas in the capped vial with a syringe, remove the solvent under vacuum, and quickly purify the residue by silica gel column chromatography to obtain 4-cyanophenyl 2-((pentafluorosulfonyl)methyl)acrylate, a white solid, with a yield of 87%. The structural formula is:

[0064] 。

[0065] 1 H NMR (600 MHz, CDCl3) 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,CDCl3) 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, CDCl3) δ 82.57 – 80.34 (m, 1F), 64.28 (d, J = 145.2 Hz,4F).

[0066] Example 6

[0067] Synthesis method of methyl 4-((2-((pentafluorosulfonyl)methyl)acryloyl)oxy)benzoate, comprising the following steps:

[0068] Under a nitrogen atmosphere, 144.4 mg of methyl 4-((2-((phenylsulfonylmethyl)acryloyl)oxy)benzoate and 4.0 mL of acetonitrile were added to a capped vial equipped with a magnetic stir bar. The vial was capped and crimped with a crimper, then taken out of the glove box. 2.0 mL of a n-hexane solution of SF5Cl with a concentration of 0.3 M was injected into the mixture. The reaction flask 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 syringe needle, and the solvent was removed under vacuum. The residue was purified rapidly by silica gel column chromatography to obtain methyl 4-((2-((pentafluorosulfonyl)methyl)acryloyl)oxy)benzoate as a white solid in 97% yield. The structural formula is:

[0069] .

[0070] 1 H NMR (600 MHz, CDCl3) 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, CDCl3) 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, CDCl3) δ 84.90 – 79.44 (m, 1F), 64.23 (d, J =145.2 Hz, 4F).

[0071] Example 7

[0072] A method for synthesizing 4-(methylsulfonyl)phenyl-2-((pentafluorosulfonyl)methyl)acrylate, comprising the following steps:

[0073] Under a nitrogen atmosphere, 228.0 mg of 4-(methylsulfonyl)phenyl 2-((phenylsulfonyl)methyl)acrylate and 6.0 mL of acetonitrile were added to a capped vial equipped with a magnetic stir bar. The vial was capped and crimped with a crimper, removed from the glove box, and 3.0 mL of a n-hexane solution of SF5Cl with a concentration of 0.3 M was injected into the mixture. The reaction flask was placed in sunlight and stirred vigorously for 15 s. After the reaction was complete, the gas in the capped vial was carefully vented with a needle, the solvent was removed in vacuo, and the residue was purified rapidly by silica gel column chromatography to give the target product 4-(methylsulfonyl)phenyl 2-((pentafluorosulfonyl)methyl)acrylate as a white solid in 76% yield. The structural formula is:

[0074] 。

[0075] 1 H NMR (600 MHz, CDCl3) 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, CDCl3) 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, CDCl3) δ 82.51 – 81.12 (m, 1F), 63.68 (dt, J =144.1, 6.8 Hz, 4F).

[0076] Example 8

[0077] N- A method for synthesizing methyl 2-[(pentafluorosulfonyl)methyl]-N-phenylacrylamide, comprising the following steps:

[0078] Under a nitrogen atmosphere, 189.0 mg of N-methyl-2-[(phenylsulfonyl)methyl]-N-phenylacrylamide and 6.0 mL of acetonitrile were added to a capped vial equipped with a magnetic stir bar. The vial was capped and crimped with a crimper, then removed from the glove box. 3.0 mL of a n-hexane solution of SF5Cl with a concentration of 0.3 M was injected into the mixture. The reaction flask was placed in sunlight and stirred vigorously for 15 s. After the reaction was completed, the gas in the capped vial was carefully discharged with a syringe, and the solvent was removed under vacuum. The residue was purified rapidly by silica gel column chromatography to obtain the target product N -Methyl-2-[(pentafluorosulfonyl)methyl]-N-phenylacrylamide, a white solid, with a yield of 66%. The structural formula is:

[0079] .

[0080] 1 H NMR (600 MHz, CDCl3) 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, CDCl3) 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, CDCl3) δ83.38 – 81.88 (m, 1F), 65.76 (dt, J = 145.2, 7.1 Hz, 4F).

[0081] Example 9

[0082] N Synthetic method of -4-bromo-N-methyl-2-[(pentafluorosulfonyl)methyl]acrylamide, comprising the following steps:

[0083] Under a nitrogen atmosphere, 196.5 mg of N-4-bromo-N-methyl-2-[(phenylsulfonyl)methyl]acrylamide and 6.0 mL of acetonitrile were added to a capped vial equipped with a magnetic stir bar. The vial was capped and crimped with a crimper, removed from the glove box, and 3.0 mL of a n-hexane solution of SF5Cl with a concentration of 0.3 M was injected into the mixture. The reaction flask was placed in 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 under vacuum, and the residue was purified rapidly by silica gel column chromatography to obtain the target product N -4-bromo-N-methyl-2-[(pentafluorosulfur)methyl]acrylamide, a white solid, with a yield of 54%. The structural formula is:

[0084] .

[0085] 1 H NMR (600 MHz, CDCl3) 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, CDCl3) 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, CDCl3) δ 84.51 – 80.14 (m, 1F), 65.07 (d, J =144.0 Hz, 4F).

[0086] Example 10

[0087] A method for synthesizing 2-((pentafluorothio)methyl)benzenesulfonylacrylic acid, comprising the following steps:

[0088] Under a nitrogen atmosphere, 258.4 mg of 2-((phenylsulfonyl)methyl)phenylsulfonylacrylic acid and 8.0 mL of acetonitrile were added to a capped vial equipped with a magnetic stir bar. The vial was capped and crimped with a crimper, then removed from the glove box. 4.0 mL of a n-hexane solution of SF5Cl with a concentration of 0.3 M was injected into the mixture. The reaction flask 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 syringe needle, the solvent was removed under vacuum, and the residue was purified rapidly by silica gel column chromatography to obtain the target product 2-((pentafluorothio)methyl)phenylsulfonylacrylic acid, a white solid, with a yield of 89%. The structural formula is:

[0089] .

[0090] 1 H NMR (600 MHz, CDCl3) δ 7.90 (d, J 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, CDCl3) δ 142.6, 138.2, 134.7, 134.4, 129.6, 128.8, 67.9 – 67.1 (m). 19 F NMR (565 MHz, CDCl3) δ 81.01 – 79.18 (m, 1F), 65.94 (dd, J J = 152.5, 6.1 Hz, 4F).

[0091] Example 11

[0092] A method for synthesizing 2-((pentafluorothio)methyl)benzyl acrylate, comprising the following steps:

[0093] Under a nitrogen atmosphere, 190.2 mg of 2-((phenylsulfonyl)methyl)benzyl acrylate and 6.0 mL of acetonitrile were added to a capped vial equipped with a magnetic stir bar. The vial was capped and crimped with a crimper, then removed from the glove box. 3.0 mL of a n-hexane solution of SF5Cl with a concentration of 0.3 M was injected into the mixture. The reaction flask 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 syringe needle, the solvent was removed under vacuum, and the residue was purified rapidly by silica gel column chromatography to obtain the target product 2-((pentafluorothio)methyl)benzyl acrylate, a colorless liquid, with a yield of 91%. The structural formula is:

[0094] 。

[0095] 1 1H NMR (600 MHz, CDCl3) 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 13C NMR (151 MHz, CDCl3) 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 19F NMR(565 MHz, CDCl3) δ 83.01 – 80.64 (m, 1F), 64.13 (dt, J = 145.1, 7.2 Hz, 4F).

[0096] Example 12

[0097] A method for synthesizing allyl pentafluorosulfanyl compounds, comprising the following steps:

[0098] Under a nitrogen atmosphere, 103.33 mg of 3-phenylpropyl 2-((phenylsulfonyl)methyl)acrylate and 3.0 mL of acetonitrile were added to a capped vial equipped with a magnetic stir bar. The vial was capped and crimped with a crimper, removed from the glove box, and 1.5 mL of a n-hexane solution of SF5Cl with a concentration of 0.3 M was injected into the mixture. The reaction flask was placed in sunlight and stirred vigorously for 15 s. After the reaction was completed, the gas in the capped vial was carefully discharged with a syringe, the solvent was removed under vacuum, and the residue was rapidly purified by silica gel column chromatography to obtain the target product 3-phenylpropyl 2-((pentafluorosulfanyl)methyl)acrylate, a colorless liquid, with a yield of 81%. The structural formula is:

[0099] 。

[0100] 1 1H NMR (600 MHz, CDCl3) 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). 1313C NMR (151 MHz, CDCl3) 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 19F NMR (565 MHz, CDCl3) δ 82.81 – 81.14 (m, 1F), 64.12 (d, J J = 145.0 Hz, 4F).

[0101] Example 13

[0102] Synthesis method of 7-hydroxycoumarin-2-((pentafluorothio)methyl)acrylate, comprising the following steps:

[0103] Under a 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 stir bar, cover the vial cap and tighten it with a crimper, take it out of the glove box, inject 3.0 mL of a n-hexane solution of SF5Cl into the mixture, where the concentration of SF5Cl is 0.3 M, place the reaction flask under sunlight and stir vigorously for 15 s; after the reaction is completed, carefully discharge the gas in the capped vial with a syringe needle, remove the solvent under vacuum, and quickly purify the residue by silica gel column chromatography to obtain the target product 7-hydroxycoumarin-2-((pentafluorothio)methyl)acrylate, a white solid, with a yield of 89%. The structural formula is:

[0104] .

[0105] 1 1H NMR (600 MHz, CDCl3) δ 7.70 (d, J J = 9.4 Hz, 1H), 7.51 (d, J J = 8.5 Hz, 1H), 7.15 (s, 1H), 7.09 (d, J 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 13C NMR (151 MHz, CDCl3) 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 19F NMR (565 MHz, CDCl3) δ 82.38 – 80.90 (m, 1F), 64.29 (dt, J J = 145.1, 6.0 Hz, 4F).

[0106] Example 14

[0107] Synthesis method of methyl tyrosine-2-((pentafluorothio)methyl)acrylate, comprising the following steps:

[0108] Under a nitrogen atmosphere, add 322.2 mg of methyl tyrosine-2-((phenylsulfonyl)methyl)acrylate and 6.0 mL of acetonitrile to a capped vial equipped with a magnetic stirrer. Cover the vial with a cap and tighten it with a crimper. Remove it from the glove box, inject 3.0 mL of a n-hexane solution of SF5Cl with a concentration of 0.3 M into the mixture. Place the reaction flask under sunlight and stir vigorously for 15 s. After the reaction is completed, carefully discharge the gas in the capped vial with a syringe, remove the solvent under vacuum, and quickly purify the residue by silica gel column chromatography to obtain the target product methyl tyrosine-2-((pentafluorothio)methyl)acrylate, a white solid, with a yield of 82%. The structural formula is:

[0109] .

[0110] 1 1H NMR (600 MHz, CDCl3) δ 7.39 – 7.30 (m, 5H), 7.13 (d, J J = 8.4 Hz, 2H), 7.05 (d, J J = 8.5 Hz, 2H), 6.83 (s, 1H), 6.21 (s, 1H), 5.23 (d, J J = 7.7 Hz, 1H), 5.10 (m, 2H), 4.73 – 4.60 (m, 3H), 3.73 (s, 3H), 3.13 (ddd, J J = 40.9, 13.9, 5.7 Hz, 2H). 13 13C NMR (151 MHz, CDCl3) 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. 1919F NMR (565 MHz, CDCl3) δ 85.77 – 79.00 (m, 1F), 64.24 (dt, J J = 145.1 Hz, 6.1 Hz, 4F).

[0111] Example 15

[0112] Synthesis method of 4-hydroxycoumarin-2-((pentafluorothio)methyl)acrylate, comprising the following steps:

[0113] Under a 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 stir bar, cover the vial cap and tighten it with a crimper, take it out of the glove box, inject 3.0 mL of a n-hexane solution of SF5Cl with a concentration of 0.3 M into the mixture, place the reaction flask under sunlight and stir vigorously for 15 s; after the reaction is completed, carefully discharge the gas in the capped vial with a syringe, remove the solvent under vacuum, and quickly purify the residue by silica gel column chromatography to obtain the target product 4-hydroxycoumarin-2-((pentafluorothio)methyl)acrylate, a white solid, with a yield of 79%. The structural formula is:

[0114] .

[0115] 1 1H NMR (600 MHz, CDCl3) δ 7.71 (d, J J = 9.5 Hz, 1H), 7.52 (dd, J J = 8.4, 2.2Hz, 1H), 7.17 (d, J J = 4.0 Hz, 1H), 7.10 (dd, J 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 J = 7.0 Hz, 2H). 13 13C NMR (151 MHz,CDCl3) 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 19F NMR (565 MHz, CDCl3) δ 83.06 – 80.50(m, 1F), 64.31 (d,J = 145.1 Hz, 4F).

[0116] Example 16

[0117] Synthesis method of RU 58841-2-((pentafluorothio)methyl)acrylate, comprising the following steps:

[0118] Under a nitrogen atmosphere, add 300.1 mg of RU 58841-2-((benzenesulfonyl)methyl)acrylate and 6.0 mL of acetonitrile to a capped vial equipped with a magnetic stir bar, cover the vial cap and tighten it with a crimper, take it out of the glove box, inject 3.0 mL of a n-hexane solution of SF5Cl with a concentration of 0.3 M into the mixture, place the reaction flask under sunlight and stir vigorously for 15 s; after the reaction is completed, carefully discharge the gas in the capped vial with a syringe needle, remove the solvent under vacuum, and rapidly purify the residue by silica gel column chromatography to obtain the target product RU 58841-2-((pentafluorothio)methyl)acrylate, a white solid, with a yield of 89%. The structural formula is:

[0119] .

[0120] 1 H NMR (600 MHz, CDCl3) 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, CDCl3) 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, CDCl3) δ 82.73-81.60. (m, 1F),63.99 (d, J= 145.0 Hz, 4F), -62.06 (s, 3F).

[0121] Example 17

[0122] A method for synthesizing epiandrosterone-2-((pentafluorothio)methyl)acrylate, comprising the following steps:

[0123] Under a nitrogen atmosphere, 299.4 mg of epiandrosterone-2-((phenylsulfonyl)methyl)acrylate and 6.0 mL of acetonitrile were added to a capped vial equipped with a magnetic stir bar. The vial was capped and crimped with a crimper, removed from the glove box, and 3.0 mL of a SF5Cl n-hexane solution with a concentration of 0.3 M was injected into the mixture. The reaction flask was placed in 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 under vacuum, and the residue was purified rapidly by silica gel column chromatography to obtain the target product epiandrosterone-2-((pentafluorothio)methyl)acrylate, a white solid, with a yield of 83%. The structural formula is:

[0124] .

[0125] 1 H NMR (600 MHz, CDCl3) 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). 1313C NMR (151 MHz, CDCl3) 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 19F NMR (565 MHz, CDCl3) δ 82.92 – 80.80 (m, 1F), 64.00 (d, J J = 145.2 Hz, 4F).

[0126] Example 18

[0127] A synthetic method of testosterone-2-((pentafluorothio)methyl)acrylate, comprising the following steps:

[0128] Under a nitrogen atmosphere, 300.2 mg of testosterone-2-((phenylsulfonyl)methyl)acrylate and 6.0 mL of acetonitrile were added to a capped vial equipped with a magnetic stir bar. The vial was capped and tightened with a crimper, then removed from the glove box. 3.0 mL of a n-hexane solution of SF5Cl with a concentration of 0.3 M was injected into the mixture. The reaction flask 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 syringe, the solvent was removed under vacuum, and the residue was purified rapidly by silica gel column chromatography to obtain the target product testosterone-2-((pentafluorothio)methyl)acrylate, a white solid, with a yield of 41%. The structural formula is:

[0129] .

[0130] 1 1H NMR (600 MHz, CDCl3) δ 6.61 (s, 1H), 6.02 (s, 1H), 4.74 (t, J J = 8.5 Hz, 1H), 4.64 – 4.49 (m, 2H), 3.27 (d, J 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). 1313C NMR (151 MHz, CDCl3) 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 19F NMR (565 MHz, CDCl3) δ 82.12 (m, 1F), 64.16 (d, J J = 145.1 Hz, 4F).

[0131] To verify the bioactivity of the pentafluorosulfanyl-modified compounds against the non-fluorine motif in the key parameter IC 50 50, the present invention tested the anti-cancer activity of the SF5-containing molecules. The propyl pentafluorosulfanyl compounds prepared in Examples 13, 15 to 18 and the corresponding non-fluorine motif compounds in Examples 13, 15 to 18 were used for systematic evaluation experiments on multiple cancer cell lines. Among them, the non-fluorine motif compounds corresponding to Examples 13, 15 to 18 were named Control Group 13, Control Group 15, Control Group 16, Control Group 17 and Control Group 18.

[0132] The structural formula of Control Group 13 is shown below:

[0133] .

[0134] The structural formula of Control Group 15 is shown below:

[0135] .

[0136] The structural formula of Control Group 16 is shown below:

[0137] .

[0138] The structural formula of Control Group 17 is shown below:

[0139] .

[0140] The structural formula of Control Group 18 is shown below:

[0141] .

[0142] The propyl pentafluorosulfanyl compounds prepared in Example 13 and Examples 15 to 18, as well as the corresponding non-fluorine motifs compounds of Example 13 and Examples 15 to 18, were used for 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 respectively placed in a humidified incubator at 37 °C with 5% CO2 by volume. The 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 respectively 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. Then, 20 μL of MTT with a concentration of 5 mg / mL was added to the cell medium and treated for another 4 h. Then, the medium was discarded, and the precipitate was dissolved in DMSO. The absorbance was measured at 570 nm using a microplate reader. All experiments were independently repeated three times, and IC 50 was calculated using GraphPad Prism 8. Among them, H820 is human lung adenocarcinoma cells; MCF-7 is human breast cancer cells; PC-3 is human prostate cancer cells; Huh-7 is human liver cancer cells; PANC-1 is human pancreatic cancer cells; SMMC-7721 is human liver cancer cells.

[0143] Table 1 IC 50 Results

[0144]

[0145] To verify the biological activities of the pentafluorosulfanyl-modified compounds and the non-fluorine motifs, the present invention conducted animal experiment tests on the anti-cancer activities of the SF5-containing molecules. The testosterone-2-((pentafluorosulfanyl)methyl)acrylate compound prepared in Example 18, which is representative, was selected for mouse experiments. A patient-derived xenograft (PDX) mouse model of lung adenocarcinoma was used to evaluate the in vivo therapeutic effect and improve clinical predictability. Corn germ oil was used as control group 1, and the fluorine-free testosterone-2-methylacrylate compound was used as control group 2. There were three groups in total, with 6 mice in each group. The structure of the fluorine-free testosterone-2-methylacrylate compound is as follows:

[0146] 。

[0147] The testosterone-2-((pentafluorothio)methyl)acrylate compound, corn germ oil, and the fluorine-free testosterone-2-methylacrylate compound prepared in Example 18 were intraperitoneally injected at a dose of 40 mg / kg every 4 days, respectively. After 31 days, the tumors were removed for detection, and the results are as Figure 3 shown.

[0148] Figure 3 This is the inhibitory effect of Example 18 of the present invention on lung adenocarcinoma tumors. Figure 3 In Figure a, it is a representative gross picture of the excised tumors of lung adenocarcinoma tumor mice after different treatments. In Figure b, it is a tumor growth curve of lung adenocarcinoma tumor mice after three different treatments. In Figure c, it is a body weight picture of lung adenocarcinoma tumor mice after three different treatments. As Figure 3 shown, the testosterone-2-((pentafluorothio)methyl)acrylate compound prepared in Example 18 significantly reduced the tumor volume, and the tumor inhibition rate was about 60%. In contrast, the experimental results of the corn germ oil and fluorine-free testosterone-2-methylacrylate compound control groups were similar, and the tumor growth increased rapidly. These results indicate that the SF5 modifier is effective in cancer treatment. At the same time, during the administration period, the body weight of the mice remained consistent with that of the control group, indicating that the drug has 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.

[0149] Although the preferred embodiments of the present invention have been described, those skilled in the art can make additional changes and modifications once they learn the basic creative concept. Therefore, the appended claims are intended to be construed to include the preferred embodiments as well as all changes and modifications falling within the scope of the present invention.

[0150] 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 equivalent technologies, the present invention also intends to include these modifications and variations.

Claims

1. An allyl pentafluorosulfanyl compound, characterized in that, The structural formula of the allyl pentafluorosulfanyl compound is as follows:

2. A method for preparing the allyl pentafluorosulfanyl compound according to claim 1, characterized in that, It includes the following steps: Using an allyl compound and a hexane solution of sulfur pentafluorochloride as raw materials, the concentration of sulfur pentafluorochloride is 0.2 M to 0.5 M. Under visible light induction in acetonitrile, an allyl pentafluorosulfanylation reaction is carried out at room temperature to obtain an allyl pentafluorosulfanyl compound in one step; The allyl compound is 7-hydroxycoumarin-2-((phenylsulfonyl)methyl)acrylate, 4-hydroxycoumarin-2-((phenylsulfonyl)methyl)acrylate, RU 58841-2-((phenylsulfonyl)methyl)acrylate, epiandrosterone-2-((phenylsulfonyl)methyl)acrylate or testosterone-2-((phenylsulfonyl)methyl)acrylate.

3. The synthesis method of the allyl pentafluorosulfanyl compound according to claim 2, wherein The molar ratio of the allyl compound to the pentafluorosulfanyl source is 0.1:0.1 to 0.

15.

4. The synthesis method of the allyl pentafluorosulfanyl compound according to claim 2, characterized in that, The wavelength of the visible light is 380 nm to 760 nm.

5. The synthesis method of the allyl pentafluorosulfanyl compound according to claim 2, wherein The time of light induction is 1 s to 15 s.

6. Use of the allyl pentafluorosulfanyl compound according to claim 1 in the preparation of an anti-tumor drug.

Images