Beta-pyridine alkyl phosphine sulfur compound as well as preparation method and anti-tumor application thereof

Abstract

The invention discloses a beta-pyridine alkyl phosphine sulfur compound as well as a preparation method and anti-tumor application thereof, and belongs to the technical field of organic synthesis and application. The structural formula of the beta-pyridine alkyl phosphine sulfur compound is shown in the specification. Wherein R1 is aryl or heteroaryl; r2 is methyl or hydrogen; r3 is methyl, chlorine or fluorine; and R4 is a phenyl group, a 3.5-dimethyl phenyl group or a cyclohexyl group. An olefin compound, a 4-cyanopyridine compound, powdered sulfur and a disubstituted phosphine hydrogen compound are used as reaction raw materials, alkali and a photocatalyst are added, a blue LED lamp irradiation reaction is performed in an inert atmosphere, and a reaction solution is concentrated, separated and purified to obtain the beta-pyridine alkyl phosphine sulfur compound. The beta-pyridine alkyl phosphine sulfur compound has human liver cancer cells HepG2 and has obvious anti-tumor activity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis and application, and particularly relates to a kind of β-pyridine alkyl phosphine sulfide compound, preparation method and its antitumor application. BACKGROUND

[0002] Pyridine is a kind of aromatic heterocyclic compound with great value, because it has electronic isosteric property with benzene ring, the structural modification of pyridine ring can often significantly improve the biological activity of drug molecules, and it has been widely used in drug molecule design. Compounds containing pyridine structure have wide biological activity and pharmacological potential, such as anticancer, antiviral, antifungal, antituberculosis, insecticidal and other biological activities, which has attracted the attention of chemists. In recent years, researchers have used 4-cyanopyridine as raw material to provide an effective synthesis strategy for pyridine-containing alkyl compounds through carbon-carbon or carbon-silicon bifunctional reactions of olefins (Org. Lett. 2022, 24, 7677 7684; Org. Lett. 2022, 24, 7145 7150; Chin. J. Catal. 2022, 43, 571–583; Org. Lett. 2024, 26, 6477 6481; J. Org. Chem. 2023, 88, 16410 16423; Chin. Chem. Lett. 2023, 34, 107822). On the other hand, alkyl phosphine sulfide compounds, as an important organic phosphine sulfur molecule, have shown important application value in drug chemistry and material science. However, there has been no report on the one-pot construction of alkyl phosphine sulfide compounds containing pyridine skeleton structure by olefin carbon-phosphine reaction using simple and readily available raw materials.

[0003] Therefore, it has certain application potential in the fields of organic synthesis and biological medicine to develop a simple and efficient method for constructing alkyl phosphine sulfide compounds containing pyridine structure skeleton. SUMMARY

[0004] In view of the problems existing in the prior art, the present application provides a kind of β-pyridine alkyl phosphine sulfide compound and its preparation method and application, with simple olefin, 4-cyanopyridine, sulfur powder and disubstituted phosphine hydrogen as raw material, visible light as clean energy, under the action of photocatalyst and base, a variety of β-pyridine alkyl phosphine sulfide compounds can be synthesized by multi-component reaction;The process raw material is cheap, the reaction condition is mild, the synthesis of β-pyridine alkyl phosphine sulfide compound is completed at room temperature, which has the advantages of clean energy, low energy consumption, no odor and simple operation.

[0005] This invention is achieved through the following technical solution: In a first aspect, the present invention provides a β-pyridinealkylphosphine sulfide compound, the structural formula of which is shown in Formula 1: Formula 1 Among them, R 1 It is aryl or heteroaryl; R 2 It is methyl or hydrogen; R 3 It is methyl, chlorine, or fluorine; R 4 It can be phenyl, 3,5-dimethylphenyl, or cyclohexyl.

[0006] In a second aspect, the present invention provides a method for preparing the β-pyridinealkylphosphine sulfur compound, characterized in that an olefin compound, a 4-cyanopyridine compound, sulfur powder and a disubstituted phosphine hydrogen compound are used as reactants, an alkali and a photocatalyst are added, the reaction is carried out under an inert atmosphere and irradiated with a blue LED lamp, and the reaction solution is concentrated, separated and purified to obtain the β-pyridinealkylphosphine sulfur compound. The structural formula of the olefin compound is shown in Formula 2: Formula 2 The structural formula of the 4-cyanopyridine compound is shown in Formula 3: Formula 3 The structural formula of the disubstituted phosphine hydrogen compound is shown in Formula 4: Formula 4 Among them, R 1 It is aryl or heteroaryl; R 2 It is methyl or hydrogen; R 3 It is methyl, chlorine, or fluorine; R 4 It can be phenyl, 3,5-dimethylphenyl, or cyclohexyl.

[0007] Further, the alkali is one or more selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropylethylamine, sodium carbonate, and potassium hydroxide, and the photocatalyst is one or more selected from eosin Y, Ru(bpy)3Cl2·3H2O, [Ir(dtbbpy)(ppy)2]PF6, and Ir[dF(CF3)ppy]2(dtbbpy)PF6.

[0008] Furthermore, the molar ratio of the olefin compound, the 4-cyanopyridine compound, the elemental sulfur, and the disubstituted phosphine hydrogen compound is 1:1~2:1~4:1~4.

[0009] Furthermore, the amount of alkali added is 100-200 mol of the amount of olefin compound; the amount of photocatalyst is 1-5 mol of the amount of olefin compound. Furthermore, the reaction is carried out in an organic solvent, which is one or more of acetonitrile, dimethyl sulfoxide, dichloromethane, toluene, and methanol.

[0010] Furthermore, the blue LED light is a 5-10W blue LED light with an irradiation response time of 1-3 hours.

[0011] Furthermore, the inert atmosphere is a nitrogen atmosphere.

[0012] Furthermore, the separation and purification method is as follows: the reaction solution is concentrated under reduced pressure to remove the organic solvent, separated by column chromatography, and washed with a mixed eluent of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 3:1 to 1:1.

[0013] In a third aspect, the present invention provides the use of the aforementioned β-pyridine alkylphosphine sulfide compound in the preparation of an antitumor drug, wherein the antitumor drug is an anti-liver tumor drug.

[0014] Compared with the prior art, the beneficial effects achieved by the present invention are as follows: (1) This invention utilizes visible light as a clean energy source and employs a photocatalyst and a base to achieve a one-step reaction of four components—olefins, 4-cyanopyridine, sulfur powder, and disubstituted phosphine hydrogen—to synthesize a series of β-pyridine alkylphosphine sulfur compounds.

[0015] (2) The method of preparing β-pyridine alkyl phosphine sulfur compounds in this invention does not require heating and can complete the synthesis of β-pyridine alkyl phosphine sulfur compounds at room temperature. It has the advantages of cheap and readily available raw materials, high reaction efficiency, odorless, mild conditions and low energy consumption. The obtained product β-pyridine alkyl phosphine sulfur compounds have human liver cancer cells HepG2 and have obvious anti-tumor activity. Attached Figure Description

[0016] Figure 1 The diagram shows the inhibitory activity of β-pyridine alkylphosphine sulfides against HepG2. Figure 2 The graph shows the inhibitory activity of compounds 5g, 5m, and 5p at different concentrations on HepG2. Detailed Implementation

[0017] The present invention is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods not specifically described in the following examples are generally performed under conventional conditions or as recommended by the manufacturer.

[0018] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of skill in the art. All reagents and materials used in this invention are readily available through conventional means, and unless otherwise specified, they shall be used in accordance with conventional methods in the art or as per the product instructions.

[0019] Example 1 In a 25 mL reaction tube, styrene 1a (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), and photocatalyst eosin Y (0.002 mmol) were added sequentially. 、 The mixture was thoroughly mixed with methanol (2 mL) as solvent, and the air in the reaction tube was replaced with nitrogen. The reaction was then irradiated with a 10W blue LED lamp and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, followed by rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfide compound 5a, a colorless oil, 18.4 mg, with a yield of 46%. The reaction formula is shown below: The NMR results of the 5a sample prepared in the example are as follows: 1 H NMR (500 MHz, CDCl3) 8.28 (d, J = 5.5Hz, 2H), 7.67-7.63 (m, 4H), 7.41-7.35 (m, 2H), 7.31-7.27 (m, 4H), 7.16-7.11(m, 4H), 7.10-7.07 (m, 3H), 4.96-4.90 (m, 1H), 3.27-3.19 (m, 2H). 13 C NMR (125MHz, CDCl3) δ 152.4 (d, J = 7.5 Hz), 149.4, 141.9 (d, J = 8.7 Hz), 132.4 (d, J =36.0 Hz), 132.1 (d, J = 35.2 Hz), 131.5 (d, J = 3.0 Hz), 131.3 (d, J = 3.0 Hz), 131.1 (d, J = 10.3 Hz), 131.0 (d,J = 10.4 Hz), 128.7, 128.5, 128.4, 128.0,127.1, 123.4, 44.7, 37.9 (d, J = 54.7 Hz). 31 P NMR (202 MHz, CDCl3): δ 41.2. ESIHRMS: calculated for C 25 H 23 NPS [M+H] + 400.1289, found 400.1288.

[0020] Example 2 Compared with Example 1, Example 2 added Ir[dF(CF3)ppy]2(dtbbpy)PF6 to replace eosin Y, with an amount of 0.002 mmol. The remaining operating conditions and steps were the same as in Example 1, and product 5a, 28.0 mg, was obtained with a yield of 81%.

[0021] Example 3 Compared with Example 1, Example 3 added Ir[dF(CF3)ppy]2(dtbbpy)PF6 to replace eosin Y, with an amount of 0.001 mmol, and replaced DBU with Na2CO3 as the base. The remaining operating conditions and steps were the same as in Example 1, and the product 5a was prepared, with a yield of 48%, and a weight of 19.1 mg.

[0022] Example 4 Compared with Example 1, Example 4 added Ru(bpy)3Cl2·3H2O to replace eosin Y, with an amount of 0.002 mmol, diisopropylethylamine as the base, toluene as the solvent, and a time of 1 hour. The remaining operating conditions and steps were the same as in Example 1, and product 5a was prepared, with a yield of 38%, and a weight of 15.1 mg.

[0023] Example 5 Compared with Example 1, in Example 5, the amount of 4-cyanopyridine 2a added was 0.1 mmol, the amount of diphenylphosphine hydrogen 4 added was 0.4 mmol, the amount of Ir[dF(CF3)ppy]2(dtbbpy)PF6 added was 0.002 mmol, the base was Et3N, the solvent was dimethyl sulfoxide, the reaction was stirred for 2 h under 5W blue LED light irradiation, and the remaining operating conditions and steps were the same as in Example 1, and product 5a was prepared, 20.3 mg, with a yield of 51%.

[0024] Example 6 Compared with Example 1, in Example 6, Ir[dF(CF3)ppy]2(dtbbpy)PF6 replaced eosin Y, the amount added was 0.002 mmol, potassium hydroxide (0.2 mmol), the solvent was acetonitrile, the time was 3 hours, and the remaining operating conditions and steps were the same as in Example 1. Product 5a was prepared, 11.6 mg, with a yield of 29%.

[0025] Example 7 Compared with Example 1, the photocatalyst in Example 7 was [Ir(dtbbpy)(ppy)2]PF6 instead of eosin Y, with an addition amount of 0.002 mmol, and the solvent was dichloromethane. The remaining operating conditions and steps were the same as in Example 1, and product 5a, 25.5 mg, was obtained with a yield of 64%.

[0026] Example 8 In a 25 mL reaction tube, p-methoxystyrene 1b (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was replaced with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under vacuum to remove the organic solvent, and the crude product was obtained. The crude product was washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 1:1, and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5b, a colorless oil, 25.8 mg, yield 60%. The reaction formula is shown below: The NMR results of 5b prepared in Example 8 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.23 ​​(s,2H), 7.62-7.53 (m, 4H), 7.35-7.29 (m, 2H), 7.25-7.19 (m, 4H), 7.04 (d, J = 5.0Hz, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.58-6.54 (m, 2H), 4.85-4.79 (m, 1H), 3.64(s, 3H), 3.15-3.10 (m, 2H). 13C NMR (125 MHz, CDCl3) δ 158.5, 148.8, 133.6 (d, J = 7.0 Hz), 132.4 (d, J = 50.4 Hz), 131.9 (d, J = 51.6 Hz), 131.5 (d, J = 2.7Hz), 131.1 (d, J = 3.0 Hz), 131.0 (d, J = 3.9 Hz), 130.9 (d, J = 3.9 Hz), 129.1,128.5, 128.4, 128.3, 128.2, 114.1, 55.2, 43.9, 38.1 (d, J = 54.7 Hz). 31 P NMR (202 MHz, CDCl3): δ 41.1. ESI HRMS: calculated for C 26 H 25 NOPS [M+H] + 430.1394, found 430.1392.

[0027] Example 9 In a 25 mL reaction tube, p-tert-butylstyrene 1c (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5c, a colorless oil, 35.1 mg, yield 77%. The reaction formula is shown below: The NMR results of the 5c sample prepared in Example 9 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.23 ​​(d, J= 4.6 Hz, 2H), 7.61 - 7.53 (m, 4H), 7.33 (t, J = 7.4 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.25 - 7.17 (m, 4H), 7.08 (d, J = 5.6 Hz, 2H), 7.05 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 4.88 - 4.82 (m, 1H), 3.22 - 3.09 (m, 2H), 1.15 (s, 9H). 13 C NMR (125 MHz, CDCl3) δ 149.9, 148.8 (d, J [[ID=]14]= 8.9 Hz), 132.6 (d, J = 37.4 Hz), !32.1 (d, J = 38.0 Hz), 131.5 (d, J = 2.9 Hz), 131.2 (d, J = 2.8 Hz), 131.1 (d, J = 5.8 Hz), 131.0 (d, J = 5.6 Hz), 128.5, 128.4, 128.3, 128.2, 127.7, 125.6, 123.7, 44.4, 38.0 (d, J = 54.7 Hz), 34.3, 31.3. 31 P NMR (202 MHz, CDCl3): δ [[ID=]32]41.2. ESI HRMS: calculated for C 29 H 31 NPS [M + H] + 456.1915, found 456.1913。

[0028] Example 10 It should be noted that there seems to be a small error in the original text where "!32.1 (d," should probably be "132.1 (d,". This has been corrected in the translation as much as possible while maintaining the integrity of the original text structure for patent translation requirements.In a 25 mL reaction tube, p-methylstyrene 1d (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate (volume ratio 2:1), and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5d, a colorless oil, 30.2 mg, yield 73%. The reaction formula is shown below: The 5-day NMR results prepared in Example 10 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.20 (d, J =5.3 Hz, 2H), 7.61-7.53 (m, 4H), 7.32-7.27 (m, 2H), 7.23-7.19 (m, 4H), 7.02(d, J = 5.8 Hz, 2H), 6.95 (d, J = 8.1 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 4.84-4.79 (m, 1H), 3.18-3.10 (m, 2H), 2.14 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 152.9(d, J = 7.8 Hz), 149.1, 138.9 (d, J = 8.8 Hz), 136.7, 132.8 (d, J = 27.8), 132.1(d, J = 27.0 Hz), 131.4 (d, J = 2.9 Hz), 131.1 (d, J = 6.4 Hz), 131.0 (d, J = 2.9Hz), 130.9 (d, J= 6.4 Hz), 129.3, 128.5, 128.4, 128.3, 128.2, 127.9, 123.5,44.3, 37.9 (d, J = 54.9 Hz), 20.9. 31 P NMR (202 MHz, CDCl3): δ 41.1. ESI HRMS:calculated for C 26 H 25 NPS [M+H] + 414.1445, found 414.1432.

[0029] Example 11 In a 25 mL reaction tube, 3-methylstyrene 1e (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate (2:1 v / v), and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5e, a colorless oil, 28.9 mg, yield 70%. The reaction formula is shown below: The NMR results of 5e prepared in Example 11 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.28 (d, J =6.0 Hz, 2H), 7.68-7.62 (m, 4H), 7.39-7.35 (m, 2H), 7.32-7.26 (m, 4H), 7.08(d, J = 6.1 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 7.8 Hz, 1H), 6.91(s, 1H), 6.88 (d, J= 7.5 Hz, 1H), 4.91-4.85 (m, 1H), 3.23-3.19 (m, 2H), 2.18(s, 3H). 13 C NMR (125 MHz, CDCl3) δ 152.5 (d, J = 7.8 Hz), 149.4, 141.8 (d, J =8.5 Hz), 138.3, 132.8 (d, J = 10.1 Hz), 132.1 (d, J = 9.6 Hz), 131.4 (d, J = 3.0Hz), 131.2 (d, J = 3.0 Hz), 131.0 (d, J = 58.6 Hz), 130.9 (d, J = 59.1 Hz),128.8, 128.6, 128.5, 128.4, 128.3, 128.2, 127.8, 125.0, 123.4, 44.6, 37.9 (d, J = 54.7 Hz), 21.3. 31 P NMR (202 MHz, CDCl3): δ 41.2. ESI HRMS: calculated for C 26 H 25 NPS [M+H] + 414.1445, found 414.1443.

[0030] Example 12 In a 25 mL reaction tube, 2-methylstyrene 1f (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate (volume ratio 2:1), and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5f, a colorless oil, 24.7 mg, yield 60%. The reaction formula is shown below: The NMR results of the 5f sample prepared in Example 12 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.16 (d, J =5.6 Hz, 2H), 7.63-7.54 (m, 4H), 7.35-7.28 (m, 2H), 7.25-7.20 (m, 4H), 7.12-7.09 (m, 1H), 7.01 (d, J = 6.0 Hz, 2H), 6.96 (m, 3H), 5.15-5.08 (m, 1H), 3.19-3.16 (m, 1H), 3.13-3.06 (m, 1H), 2.20 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 152.5(d, J = 5.5 Hz), 149.0, 140.0 (d, J = 8.8 Hz), 136.4, 132.7 (d, J = 81.5 Hz), 131.8 (d, J = 83.9 Hz), 131.5 (d, J = 2.9 Hz), 131.3 (d, J = 3.0 Hz), 131.1 (d, J = 10.1 Hz), 130.9 (d, J = 10.2 Hz), 128.5, 128.4, 127.1, 126.9, 126.2, 123.8,40.3, 38.6 (d, J = 54.3 Hz), 20.0. 31 P NMR (202 MHz, CDCl3): δ 41.6. ESI HRMS:calculated for C 26 H 25 NPS [M+H] + 414.1445, found 414.1435.

[0031] Example 13 In a 25 mL reaction tube, 1 g (0.1 mmol) of 4-fluorostyrene, 2a (0.2 mmol) of 4-cyanopyridine, 3 (0.3 mmol) of sulfur powder, 4a (0.2 mmol) of diphenylphosphine hydrogen, 0.2 mmol of base DBU, 0.002 mmol of photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mL) of solvent, and 2 mL of solvent were added sequentially and mixed thoroughly. The air in the reaction tube was replaced with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, and subjected to rapid silica gel column chromatography to obtain 5 g of β-pyridinealkylphosphine sulfur compound as a colorless oil, 32.2 mg, with a yield of 77%. The reaction formula is shown below: The NMR results of the 5g sample prepared in Example 13 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.27 (d, J =3.0 Hz, 2H), 7.63-7.45 (m, 4H), 7.33-7.30 (m, 2H), 7.26-7.19 (m, 4H), 7.07(d, J = 4.9 Hz, 2H), 7.04-6.99 (m, 2H), 6.70 (t, J = 8.6 Hz, 2H), 4.91-4.86 (m,1H), 3.18-3.07 (m, 2H). 13 C NMR (125 MHz, CDCl3) δ 161.8 (d, J = 244.5 Hz), 148.7, 137.1 (d, J = 7.5 Hz), 137.0 (d, J = 7.3 Hz), 132.5 (d, J = 70.0 Hz), 131.8 (d, J = 69.6 Hz), 131.7 (d, J = 2.9 Hz), 131.3 (d, J = 3.0 Hz), 131.1 (d, J = 10.4 Hz), 130.9 (d, J = 10.2 Hz), 129.8 (d, J= 8.3 Hz), 128.6, 128.5, 128.4,128.3, 123.5, 115.5 (d, J = 21.3 Hz), 44.0, 38.0 (d, J = 54.8 Hz). 31 P NMR (202MHz, CDCl3): δ 40.9. ESI HRMS: calculated for C 25 H 22 FNPS [M+H] + 418.1195, found418.1192.

[0032] Example 14 In a 25 mL reaction tube, 3-fluorostyrene 1h (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate (volume ratio 2:1), and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5h, a colorless oil, 26.8 mg, yield 64%. The reaction formula is shown below: The NMR results prepared in Example 14 after 5 hours are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.25 (d, J =4.4 Hz, 2H), 7.61-7.57 (m, 4H), 7.35-7.29 (m, 2H), 7.23 (t, J = 6.7 Hz, 4H), 7.03 (d, J = 5.6 Hz, 2H), 7.01 (t, J = 7.0 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.75 (d, J= 9.9 Hz, 1H), 6.71 - 6.66 (m, 1H), 4.90 - 4.85 (m, 1H), 3.17 - 3.08 (m, 2H). 13 C NMR (125 MHz, CDCl3) δ 162.7 (d, J = 245.4 Hz), 152.4 (d, J = 7.0 Hz), 149.1, 144.1 (d, J = 7.9 Hz), 132.5 (d, J = 20.5 Hz), 131.9 (d, J = 20.5 Hz), 131.6 (d, J = 2.9 Hz), 131.4 (d, J = 2.9 Hz), 131.1 (d, J = 1.6 Hz), 131.0 (d, J = 1.5 Hz), 130.2 (d, J = 8.2 Hz), 128.6, 128.5, 128.4, 123.9 (d, J = 2.7 Hz), 123.4, 115.0 (d, J = 21.7 Hz), 114.1 (d, J = 20.9 Hz), 44.6, 37.7 (d, J = 54.9 Hz). 31 P NMR (202 MHz, CDCl3): δ 40.9. ESI HRMS: calculated for C 25 H 22 FNPS [M + H] + 418.1195, found 418.1193。

[0033] Example 15 In a 25 mL reaction tube, 4-chlorostyrene 1i (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate (volume ratio 2:1) as eluent, and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5i, a colorless oil, 33.0 mg, yield 76%. The reaction formula is shown below: The NMR results of the 5i prepared in Example 15 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.27 (d, J =4.5 Hz, 2H), 7.63-7.58 (m, 2H), 7.57-7.50 (m, 2H), 7.36-7.32 (m, 2H), 7.27-7.20 (m, 4H), 7.08 (d, J = 5.0 Hz, 2H), 6.97 (s, 4H), 4.90-4.85 (m, 1H), 3.19-3.06 (m, 2H). 13 C NMR (125 MHz, CDCl3) δ 148.5, 139.7 (d, J = 4.2 Hz), 132.9 (d, J = 42.3 Hz), 131.9 (d, J = 45.1 Hz), 131.7 (d, J = 2.9 Hz), 131.4, 131.3 (d, J = 2.9 Hz), 131.1 (d, J = 10.2 Hz), 130.9 (d, J = 10.2 Hz), 129.5, 128.8, 128.6,128.5, 128.4, 128.3, 123.6, 44.2, 37.8 (d, J = 55.0 Hz). 31P NMR (202 MHz, CDCl3): δ 40.8. ESI HRMS: calculated for C 25 H 22 ClNPS [M+H] + 434.0899, found434.0897.

[0034] Example 16 In a 25 mL reaction tube, 3-chlorostyrene 1j (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate (volume ratio 2:1), and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5j, a colorless oil, 28.2 mg, yield 65%. The reaction formula is shown below: The NMR results of the 5j sample prepared in Example 16 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.33 (d, J =5.7 Hz, 2H), 7.70-7.62 (m, 4H), 7.42-7.36 (m, 2H), 7.34-7.28 (m, 4H), 7.10-7.06 (m, 3H), 7.05-7.00 (m, 3H), 4.95-4.90 (m, 1H), 3.25-3.14 (m, 2H). 13 C NMR (125 MHz, CDCl3) δ 151.7 (d, J = 8.7 Hz), 149.7, 143.6 (d, J = 7.5 Hz), 134.4, 132.4 (d, J = 74.9 Hz), 132.1 (d, J = 74.8 Hz), 131.6 (d, J = 2.8 Hz), 131.4 (d, J= 2.9 Hz), 131.1 (d, J = 10.2 Hz), 130.9 (d, J = 10.1 Hz), 129.9, 128.6,128.5, 128.4, 128.3, 128.1, 127.3, 126.6, 123.2, 44.4, 37.6 (d, J = 55.0 Hz). 31 P NMR (202 MHz, CDCl3): δ 40.9. ESI HRMS: calculated for C 25 H 22 ClNPS [M+H] + 434.0899, found 434.0885.

[0035] Example 17 In a 25 mL reaction tube, 2-chlorostyrene 1k (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate (volume ratio 2:1), and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5k, a colorless oil, 22.6 mg, yield 52%. The reaction formula is shown below: The 5k NMR results prepared in Example 17 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.21 (d, J =4.1 Hz, 2H), 7.65-7.59 (m, 4H), 7.37-7.33 (m, 1H), 7.32-7.28 (m, 1H), 7.27-7.20 (m, 5H), 7.11 (d, J= 7.4 Hz, 1H), 7.02 - 6.97 (m, 4H), 5.33 - 5.27 (m, 1H), 3.29 - 3.22 (m, 1H), 3.20 - 3.14 (m, 1H). 13 C NMR (125 MHz, CDCl3) δ 151.0 (d, J = 7.5 Hz), 149.2, 139.0 (d, J = 8.2 Hz), 134.0, 132.3 (d, J = 80.7 Hz), 132.2 (d, J = 80.2 Hz), 131.6 (d, J = 2.9 Hz), 131.6 (d, J = 53.0 Hz), 131.4 (d, J = 2.9Hz), 131.3 (d, J = 54.7 Hz), 130.2, 129.4, 128.5, 128.4, 128.3, 126.9, 123.6, 41.4, 37.9 (d, J = 54.6 Hz). 31 P NMR (202 MHz, CDCl3): δ 40.9. ESI HRMS: calculated for C 25 H 22 ClNPS [M + H] + 434.0899, found 434.0888。

[0036] Example 18 In a 25 mL reaction tube, 1 μL (0.1 mmol) of 4-bromostyrene, 2a (0.2 mmol) of 4-cyanopyridine, 3 μL (0.3 mmol) of sulfur powder, 4a (0.2 mmol) of diphenylphosphine hydrogen, 0.2 mmol of base DBU, 0.002 mmol of photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol) and 2 mL of solvent methanol were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, and subjected to rapid silica gel column chromatography to obtain 5 μL of β-pyridinealkylphosphine sulfur compound, which was a colorless oil, 28.7 mg, with a yield of 60%. The reaction formula is shown below: The NMR results of the 5l prepared in Example 18 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.28 (s,2H), 7.63-7.58 (m, 2H), 7.55-7.51 (m, 2H), 7.35 (d, J = 4.5 Hz, 2H), 7.27-7.20(m, 4H), 7.11 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 4.8 Hz, 2H), 6.91 (d, J = 7.8Hz, 2H), 4.88-4.83 (m, 1H), 3.19-3.06 (m, 2H). 13 C NMR (125 MHz, CDCl3) δ148.7, 148.6 (d, J = 6.0 Hz), 140.2 (d, J = 6.8 Hz), 132.5 (d, J = 80.0 Hz), 131.8 (d, J = 80.7 Hz), 131.7, 131.6 (d, J = 2.9 Hz), 131.3 (d, J = 2.9 Hz), 131.1 (d, J = 10.3 Hz), 130.9 (d, J= 10.6 Hz), 129.9, 128.6, 128.5, 128.4,128.3, 123.5, 121.2, 44.3, 37.8 (d, J = 55.0 Hz). 1 P NMR (202 MHz, CDCl3): δ 40.8.ESI HRMS: calculated for C 25 H 22 BrNPS [M+H] + 478.0394, found 478.0392.

[0037] Example 19 In a 25 mL reaction tube, 1m of 4-trifluoromethylstyrene (0.1 mmol), 2a of 4-cyanopyridine (0.2 mmol), 3 sulfur powder (0.3 mmol), 4a of diphenylphosphine hydrogen (0.2 mmol), 0.2 mmol of base DBU, 0.002 mmol of photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and 2 mL of solvent methanol were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, and subjected to rapid silica gel column chromatography to obtain 5m of β-pyridinealkylphosphine sulfur compound, a colorless oil, 19.2 mg, with a yield of 41%. The reaction formula is shown below: The 5 μm NMR results prepared in Example 19 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.33 (s,2H), 7.64-7.60 (m, 2H), 7.55-7.49 (m, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.31-7.24(m, 5H), 7.20-7.15 (m, 6H), 5.02-4.98 (m, 1H), 3.24-3.18 (m, 1H), 3.15-3.08(m, 1H). 13 C NMR (125 MHz, CDCl3) δ 148.0, 144.8 (d, J = 7.5 Hz), 132.6 (d, J=81.6 Hz), 131.9 (d, J = 60.9 Hz), 131.8 (d, J = 2.9 Hz), 131.5 (d, J = 3.0 Hz), 131.1 (d, J = 10.2 Hz), 130.9 (d, J = 10.1 Hz), 129.6, 128.8, 128.7, 128.6,128.5, 128.4, 125.6 (q, J = 3.7 Hz), 125.1, 123.9, 123.8, 44.7, 37.6 (d, J =54.9 Hz). 1 P NMR (202 MHz, CDCl3): δ 40.6. ESI HRMS: calculated for C 26 H 22 F3NPS [M+H] + 468.1163, found 468.1162.

[0038] Example 20 In a 25 mL reaction tube, 4-cyanostrene 1n (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 3 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate (volume ratio 2:1), and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5n, a colorless oil, 25.8 mg, yield 61%. The reaction formula is shown below: The NMR results of the 5n sample prepared in Example 20 are as follows: 11H NMR (500 MHz, CDCl3) δ 8.31 (s, 2H), 7.63 - 7.57 (m, 2H), 7.56 - 7.51 (m, 2H), 7.37 - 7.32 (m, 2H), 7.27 - 7.25 (m, 4H), 7.24 - 7.20 (m, 2H), 7.17 (d, J J = 8.3 Hz, 2H), 7.03 (d, J J = 5.6 Hz, 2H), 5.00 - 4.92 (m, 1H), 3.20 - 3.07 (m, 2H). 13 13C NMR (125 MHz, CDCl3) δ 151.5, 149.5, 146.6 (d, J J = 6.7 Hz), 132.3, 131.8 (d, J J = 2.5 Hz), 131.5 (d, J J = 2.6 Hz), 131.1 (d, J J = 10.5 Hz), 130.9 (d, J J = 10.0 Hz), 130.6, 129.1, 128.7, 128.6, 128.5, 128.4, 123.3, 111.0, 44.8, 37.4 (d, J J = 54.3 Hz). 1 31P NMR (202 MHz, CDCl3): δ 40.6. ESI HRMS: calculated for C 26 H 22 N2PS [M + H] + 425.1241, found 425.1240。

[0039] Example 21 In a 25 mL reaction tube, 2-vinylthiophene 1o (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1, and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5o, a colorless oil, 26.4 mg, yield 65%; the reaction formula is shown below: The NMR results of the 5° sample prepared in Example 21 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.20 (d, J =5.4 Hz, 2H), 7.66-7.62 (m, 2H), 7.56-7.52 (m, 2H), 7.36-7.33 (m, 1H), 7.31-7.26 (m, 3H), 7.21-7.17 (m, 2H), 7.07 (d, J = 5.8 Hz, 2H), 7.00 (d, J = 4.4 Hz, 1H), 6.72 (d, J = 3.3 Hz, 1H), 6.71-6.67 (m, 1H), 5.16-5.10 (m, 1H), 3.19-3.15(m, 2H). 13 C NMR (125 MHz, CDCl3) δ 152.1 (d, J = 6.0 Hz), 149.0, 145.8 (d, J =11.6 Hz), 132.8 (d, J = 81.8 Hz), 131.6 (d, J = 80.2 Hz), 131.5 (d, J = 2.9 Hz), 131.4 (d, J = 3.0 Hz), 131.2 (d, J = 10.2 Hz), 130.9 (d,J = 10.2 Hz), 128.6,128.5, 128.4, 128.3, 126.8, 125.4, 124.8, 123.5, 40.6, 39.4 (d, J = 54.2 Hz). 1 P NMR (202 MHz, CDCl3): δ 40.4. ESI HRMS: calculated for C 23 H 21 NPS2[M+H] + 406.0853, found 406.0856.

[0040] Example 22 In a 25 mL reaction tube, 2-vinylpyridine 1p (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 3 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate (2:1 v / v), followed by rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5p, a colorless oil, 25.2 mg, with a yield of 63%. The reaction formula is shown below: The NMR results of the 5p sample prepared in Example 22 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.27 (d, J =5.6 Hz, 1H), 8.24 (d, J = 5.6 Hz, 2H), 7.66-7.56 (m, 4H), 7.35-7.30 (m, 2H), 7.26-7.22 (m, 3H), 7.20-7.16 (m, 4H), 7.02 (d, J = 7.8 Hz, 1H), 6.90-6.88 (m,1H), 4.93-4.86 (m, 1H), 3.76-3.70 (m, 1H), 3.08-3.02 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 159.6 (d, J = 5.5 Hz), 152.1 (d, J = 12.0 Hz), 149.4, 149.3, 136.5,132.7 (d, J = 50.6 Hz), 132.2 (d, J = 50.1 Hz), 131.4 (d, J = 2.9 Hz), 131.2 (d, J = 10.4 Hz), 131.1 (d, J = 3.0 Hz), 130.9 (d, J = 10.1 Hz), 128.5, 128.4,128.2, 128.1, 124.2, 123.6, 122.1, 46.6, 37.0 (d, J = 55.1 Hz). 31 P NMR (202MHz, CDCl3): δ 41.3. ESI HRMS: calculated for C 24 H 22 N2PS [M+H] + 401.1241, found 401.1230.

[0041] Example 23 In a 25 mL reaction tube, 2-vinylnaphthalene 1q (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate (volume ratio 2:1), and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5q, a colorless oil, 23.8 mg, yield 53%. The reaction formula is shown below: The NMR results of the 5q sample prepared in Example 23 are as follows: 11H NMR (500 MHz, CDCl3) δ 8.24 (d, J J = 4.3 Hz, 2H), 7.63 - 7.58 (m, 4H), 7.55 - 7.49 (m, 4H), 7.33 - 7.31 (m, 3H), 7.26 - 7.21 (m, 2H), 7.13 - 7.06 (m, 4H), 7.02 (m, 2H), 5.06 - 5.01 (m, 1H), 3.30 - 3.19(m, 2H). 13 13C NMR (125 MHz, CDCl3) δ 149.1 (d, J J = 2.4 Hz), 149.0 (d, J J = 7.1 Hz),138.9 (d, J J = 6.9 Hz), 133.2, 132.5 (d, J J = 80.8 Hz), 132.4, 132.0 (d, J J = 80.9Hz), 131.5 (d, J J = 2.8 Hz), 131.1 (d, J J = 10.4 Hz), 130.9 (d, J J = 3.0 Hz), 130.8(d, J J = 9.8 Hz), 128.6, 128.5, 128.4, 128.2, 128.1, 127.8, 127.5, 126.9,126.2, 126.0, 123.6, 44.7, 37.8 (d, J J = 54.9 Hz). 31 31P NMR (202 MHz, CDCl3): δ 41.1. ESI HRMS: calculated for C 29 H 25 NPS [M + H] + 450.1445, found 450.1439。

[0042] Example 24 In a 25 mL reaction tube, β-methylstyrene 1r (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate (volume ratio 2:1), and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5r, a colorless oil, 28.9 mg, yield 70%. The reaction formula is shown below: The NMR results of the 5r sample prepared in Example 24 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.40 (d, J =4.9 Hz, 2H), 7.96-7.89 (m, 2H), 7.58-7.52 (m, 2H), 7.37 (d, J = 2.1 Hz, 3H), 7.29 (d, J = 5.9 Hz, 2H), 7.09 (t, J = 7.1 Hz, 1H), 7.09-6.98 (m, 4H), 6.83-6.75 (m, 3H), 4.55-4.51 (m, 1H), 3.74-3.69 (m, 1H), 1.02-0.96 (m, 3H). 13 C NMR (125 MHz, CDCl3) δ 148.9 (d, J = 10.3 Hz), 140.1 (d, J = 3.5 Hz), 132.6 (d, J =78.1 Hz), 131.7 (d, J = 79.1 Hz), 131.4 (d, J = 1.3 Hz), 131.3, 130.5 (d, J =3.0 Hz), 128.9, 128.6, 128.5, 128.3, 127.9, 127.8, 127.4, 124.5, 52.3, 36.5(d,J = 54.8 Hz), 14.5. 31 P NMR (202 MHz, CDCl3): δ 53.0. ESI HRMS: calculated forC 26 H 25 NPS [M+H] + 414.1445, found 414.1442.

[0043] Example 25 In a 25 mL reaction tube, styrene 1a (0.1 mmol), 2-methyl-4-cyanopyridine 2b (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate (volume ratio 2:1), and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5s, a colorless oil, 24.8 mg, yield 60%. The reaction formula is shown below: The 5s NMR results prepared in Example 25 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.09 (d, J =5.9 Hz, 1H), 7.60-7.54 (m, 4H), 7.30-7.27 (m, 2H), 7.23-7.18 (m, 4H), 7.10-7.04 (m, 4H), 7.03-7.00 (m, 1H), 6.83 (d, J = 4.5 Hz, 2H), 4.85-4.79 (m, 1H), 3.21-3.07 (m, 2H), 2.28 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 158.0, 152.7 (d, J =7.0 Hz), 148.7, 142.2 (d, J = 9.2 Hz), 132.7 (d, J= 73.9 Hz), 132.1 (d, J =72.6 Hz), 131.5 (d, J = 3.0 Hz), 131.3 (d, J = 3.0 Hz), 131.1 (d, J = 13.5 Hz), 130.9 (d, J = 3.0 Hz), 128.7, 128.5, 128.4, 128.3, 128.2, 127.9, 127.0, 123.1,120.5, 44.7, 37.8 (d, J = 54.7 Hz), 24.1. 31 P NMR (202 MHz, CDCl3): δ 41.2. ESIHRMS: calculated for C 26 H 25 NPS [M+H] + 414.1445, found 414.1436.

[0044] Example 26 In a 25 mL reaction tube, styrene 1a (0.1 mmol), 2,6-dimethyl-4-cyanopyridine 2c (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate (volume ratio 2:1), and subjected to rapid silica gel column chromatography to obtain 5t of β-pyridinealkylphosphine sulfur compound, a colorless oil, 28.2 mg, with a yield of 66%. The reaction formula is shown below: The NMR results of the 5t sample prepared in Example 26 are as follows: 11H NMR (500 MHz, CDCl3) δ 7.63 - 7.54 (m, 4H), 7.32 - 7.27 (m, 2H), 7.24 - 7.19 (m, 4H), 7.11 - 7.05 (m, 4H), 7.04 - 6.99 (m, 1H), 6.66 (s, 2H), 4.82 - 4.74 (m, 1H), 3.20 - 3.13 (m, 1H), 3.10 - 3.07 (m, 1H), 2.26 (s, 6H). 13 13C NMR (125 MHz, CDCl3) δ 157.4, 152.8 (d, J J = 5.9 Hz), 142.4 (d, J J = 9.5 Hz), 132.9 (d, J J = 81.3 Hz), 132.1 (d, J J = 80.1 Hz), 131.4 (d, J J = 2.9 Hz), 131.3 (d, J J = 3.0 Hz), 131.1 (d, J J = 10.2 Hz), 130.9 (d, J J = 10.1 Hz), 128.6, 128.5, 128.4, 128.2, 128.1, 127.9, 126.9, 120.2, 44.6, 37.7 (d, J J = 54.7 Hz), 24.1. 31 31P NMR (202 MHz, CDCl3): δ 41.2. ESI HRMS: calculated for C 27 H 27 NPS [M + H] + 428.1602, found 428.1601。

[0045] Example 27 In a 25 mL reaction tube, styrene 1a (0.1 mmol), 3-fluoro-4-cyanopyridine 2d (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was then washed with a mixture of petroleum ether and ethyl acetate (volume ratio 2:1), followed by rapid silica gel column chromatography to obtain 5u of β-pyridinealkylphosphine sulfur compound, a colorless oil, 28.3 mg, with a yield of 68%. The reaction formula is shown below: The NMR results of the 5u sample prepared in Example 27 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.04 (d, J =4.7 Hz, 1H), 7.95 (s, 1H), 7.66-7.62 (m, 2H), 7.60-7.56 (m, 2H), 7.36-7.33(m, 1H), 7.30-7.24 (m, 3H), 7.21-7.18 (m, 2H), 7.16 (d, J = 7.5 Hz, 2H), 7.10(d, J = 7.3 Hz, 3H), 7.05 (t, J = 7.2 Hz, 1H), 5.06-4.99 (m, 1H), 3.42-3.36 (m, 1H), 3.13-3.06 (m, 1H). 13 C NMR (125 MHz, CDCl3) δ 157.5 (d, J = 254.2 Hz), 145.4 (d, J = 4.8 Hz), 142.4, 141.0 (d, J = 10.5 Hz), 138.2 (d, J = 25.1 Hz), 133.0 (d, J = 81.7 Hz), 131.6 (d, J = 80.3 Hz), 131.5 (d, J= 2.8 Hz), 131.4 (d, J = 2.9 Hz), 131.2 (d, J = 10.3 Hz), 130.9 (d, J = 10.1 Hz), 128.7, 128.6,128.5, 128.3, 128.2, 127.8, (d, J = 12.0 Hz), 127.2, 124.5 (d, J = 1.4 Hz), 40.3, 36.2 (d, J = 56.0 Hz). 31 P NMR (202 MHz, CDCl3): δ 40.6. ESI HRMS:calculated for C 25 H 22 FNPS [M+H] + 418.1195, found 418.1190.

[0046] Example 28 In a 25 mL reaction tube, styrene 1a (0.1 mmol), 3-chloro-4-cyanopyridine 2e (0.2 mmol), sulfur powder 3 (0.3 mmol), diphenylphosphine hydrogen 4a (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate (2:1 v / v) as eluent, and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5v, a colorless oil, 30.3 mg, yield 70%. The reaction formula is shown below: The NMR results of the 5V sample prepared in Example 28 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.26 (s,1H), 8.15 (s, 1H), 7.66-7.59 (m, 4H), 7.35-7.31 (m, 2H), 7.27-7.21 (m, 4H),7.13-7.09 (m, 3H), 7.07 (t J= 7.6 Hz, 2H), 7.02 (t, J = 7.1 Hz, 1H), 5.30 - 5.24(m, 1H), 3.29 - 3.27 (m, 1H), 3.19 - 3.12 (m, 1H). 13 C NMR (125 MHz, CDCl3) δ149.8, 148.9 (d, J = 7.4 Hz), 147.4, 140.4 (d, J = 8.7 Hz), 132.6 (d, J = 21.2Hz), 132.0 (d, J = 20.7 Hz), 131.5 (d, J = 2.9 Hz), 131.4 (d, J = 2.8 Hz), 130.5(d, J = 10.1 Hz), 131.1(d, J = 10.3 Hz), 128.6, 128.5, 128.4, 128.3, 128.2,128.1, 127.1, 123.7, 41.4, 37.3 (d, J = 54.5 Hz). 31 P NMR (202 MHz, CDCl3): δ 40.7. ESI HRMS: calculated for C 25 H 22 ClNPS [M + H] + 434.0899, found 434.0894。

[0047] Example 29 In a 25 mL reaction tube, styrene 1a (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), di-3,5-dimethylphenylphosphine hydrogen 4b (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate (volume ratio 2:1), and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5w, a colorless oil, 30.3 mg, yield 65%. The reaction formula is shown below: The NMR results of the 5W sample prepared in Example 29 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.29 (d, J =5.8 Hz, 2H), 7.19 (s, 2H), 7.20 (s, 2H), 7.18-7.13 (m, 4H), 7.12-7.08 (m,3H), 6.99 (d, J = 4.4 Hz, 2H), 4.93-4.86 (m, 1H), 3.19-3.15 (m, 2H), 2.23 (s, 6H), 2.22 (s, 6H). 13 C NMR (125 MHz, CDCl3) δ 152.6 (d, J = 7.2 Hz), 149.2,142.3 (d, J = 8.7 Hz), 138.1, (d, J = 1.6 Hz), 138.0 (d, J = 1.6 Hz), 133.2 (d, J = 3.0 Hz), 133.1 (d, J = 3.0 Hz), 132.4 (d, J = 45.1 Hz), 131.8 (d, J = 44.3Hz), 128.8, 128.7, 128.6, 128.5, 128.4, 128.0, 126.9, 123.4, 44.7, 38.0 (d,J = 54.4 Hz), 21.3, 21.2. 31 P NMR (202 MHz, CDCl3): δ 41.6. ESI HRMS: calculated for C 29 H 31 NPS [M+H] + 456.1915, found 456.1910.

[0048] Example 30 In a 25 mL reaction tube, styrene 1a (0.1 mmol), 4-cyanopyridine 2a (0.2 mmol), sulfur powder 3 (0.3 mmol), dicyclohexylphosphine hydrogen 4c (0.2 mmol), base DBU (0.2 mmol), photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.002 mmol), and solvent methanol (2 mL) were added sequentially and mixed thoroughly. The air in the reaction tube was purged with nitrogen, and the reaction solution was irradiated with a 10W blue LED lamp. The mixture was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated under vacuum to remove the organic solvent, yielding a crude product. The crude product was washed with a mixture of petroleum ether and ethyl acetate (volume ratio 2:1) as eluent, and subjected to rapid silica gel column chromatography to obtain β-pyridinealkylphosphine sulfur compound 5x, a colorless oil, 17.6 mg, yield 43%. The reaction formula is shown below: The NMR results of the 5x sample prepared in Example 31 are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.50 (d, J =5.8 Hz, 2H), 7.36-7.30 (m, 4H), 7.27 (d, J = 6.8 Hz, 2H), 7.23 (t, J = 7.0 Hz,1H), 4.86-4.78 (m, 1H), 2.62-2.54 (m, 1H), 2.48-2.41 (m, 1H), 1.88-1.58 (m,12H), 1.42-1.30 (m, 3H), 1.16-0.98 (m, 6H), 0.88-0.82 (m, 1H). 13 C NMR (125MHz, CDCl3) δ 154.1 (d, J = 8.3 Hz), 149.9, 142.8 (d, J= 5.1 Hz), 129.0,128.3, 127.3, 123.2, 44.2, 38.4 (d, J = 50.0 Hz), 38.0 (d, J = 46.6 Hz), 30.6(d, J = 46.7 Hz), 26.8 (d, J = 12.9 Hz), 26.7 (d, J = 9.9 Hz), 26.6 (d, J = 1.7Hz), 26.5 (d, J = 0.8 Hz), 26.4 (d, J = 4.1 Hz), 26.3 (d, J = 3.0 Hz), 26.2 (d, J = 3.1 Hz), 25.8 (d, J = 1.5 Hz), 25.7 (d, J = 1.2 Hz). 31 P NMR (202 MHz, CDCl3): Figure 1 61.0. ESI HRMS: calculated for C 25 H 35 NPS [M+H] + 412.2228, found 412.2219.

[0049] Application Examples (1) Experimental materials HepG2 cells were purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; DMEM high glucose medium / fetal bovine serum were purchased from Gibco, USA; and MTT and DMSO were purchased from Solarbio. (2) Experimental instruments Epoch microplate reader (Biotek, USA); (3) Experimental methods The effect of β-pyridine alkylphosphine sulfide compounds on the proliferation of HepG2 cells was determined using the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. HepG2 cells were incubated at 8 × 10⁻⁶ cells / year. 3Cells were seeded at a density of 100 mM / well in 96-well plates and incubated at 37°C with 5% CO2 for 24 h. β-pyridine alkylphosphine sulfide was first prepared at a concentration of 100 mM using DMSO, then dissolved in complete culture medium to initial drug concentrations of 640 μM and 320 μM, respectively. The initial concentration of the positive control drug paclitaxel (PTX) was 640 μM. All test drugs were serially diluted 2-fold (9 steps in total). Different concentrations of β-pyridine alkylphosphine sulfide were added to the seeded cells, with 6 replicates per concentration. Cells were incubated at 37°C with 5% CO2 for 48 h. After incubation, 20 μL of MTT solution (5 mg / mL) was added to each well, and the cells were incubated at 37°C for 4 h. After incubation, the supernatant was discarded, and 150 μL of DMSO was added and mixed using a shaker. Cell viability and IC50 were calculated using a microplate reader at 490 nm. 50 Values; Cell viability of β-pyridinealkylphosphine sulfur compound at a concentration of 20 μM is shown in the figure. Figure 2 As shown, 5g, 5m, 5p and PTX exhibited good inhibitory activity against the proliferation of HepG2 cells.

[0050] IC50 of β-pyridine alkylphosphine sulfur compounds 5g, 5m, 5p and PTX 50 The value results are shown in the figure. ​ As shown in the figure. It can be seen from the figure that the IC50 of compound 5m is... 50 The value was 218.7 μM (95% confidence interval 203.0–235.7), and its inhibitory effect was superior to that of paclitaxel (PTX) (IC50). 50 = 588.7 μM), which has good inhibitory activity against the proliferation of liver tumor cells.

[0051] The above description merely illustrates several embodiments of the present invention and should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make modifications, substitutions, and improvements without departing from the concept and scope of the present invention, and these all fall within the protection scope of the present invention. Therefore, the patent protection scope of the present invention should be determined by the described claims.

Claims

1. A β-pyridylalkylphosphine sulfide compound, characterized by, The structural formula of the beta-pyridine alkyl phosphine sulfur compound is shown as formula 1. Formula 1 wherein R 1 is aryl or heteroaryl; R 2 is methyl or hydrogen; R 3 is methyl, chloro or fluoro; and R 4 is phenyl, 3,5-dimethylphenyl or cyclohexyl.

2. A process for the preparation of a β-pyridylalkylphosphine sulfide compound according to claim 1, characterized in that, The beta-pyridine alkyl phosphine sulfur compound is obtained by using an olefin compound, a 4-cyanopyridine compound, sulfur powder and a disubstituted phosphine hydrogen compound as reaction raw materials, adding a base and a photocatalyst, irradiating the reaction under a blue LED lamp in an inert atmosphere, and concentrating, separating and purifying the reaction solution. The structural formula of the olefin compound is shown as formula 2. Formula 2 The structural formula of the 4-cyanopyridine compound is shown as formula 3. Formula 3 The structural formula of the disubstituted phosphine hydrogen compound is shown as formula 4. Formula 4 wherein R 1 is aryl or heteroaryl; R 2 is methyl or hydrogen; R 3 is methyl, chloro or fluoro; R 4 is phenyl, 3.5-dimethylphenyl or cyclohexyl.

3. The method of producing a β-pyridylalkylphosphine sulfide compound according to claim 2, characterized by, The base is one or more of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diisopropylethylamine, sodium carbonate and potassium hydroxide, and the photocatalyst is one or more of eosin Y, Ru(bpy)3Cl2·3H2O, [Ir(dtbbpy)(ppy)2]PF6 and Ir[dF(CF3)ppy]2(dtbbpy)PF6.

4. The method of producing a β-pyridylalkylphosphine sulfide compound according to claim 2, characterized by, The molar ratio of the olefin compound, the 4-cyanopyridine compound, the elemental sulfur and the disubstituted phosphine hydrogen compound is 1:1-2:1-4:1-4.

5. The method for producing a β-pyridylalkylphosphine sulfide compound according to claim 2, characterized by, The amount of the base added is 100-200 mol% of the amount of the olefin compound, and the amount of the photocatalyst is 1-5 mol% of the amount of the olefin compound.

6. The method of producing a β-pyridylalkylphosphine sulfide compound according to claim 2, characterized by, The reaction is carried out in an organic solvent, and the organic solvent is one or more of acetonitrile, dimethyl sulfoxide, dichloromethane, toluene and methanol.

7. The method of producing a β-pyridylalkylphosphine sulfide compound according to claim 2, characterized by, The blue LED lamp is a 5-10 W blue LED lamp, and the irradiation reaction time is 1-3 hours.

8. The method of producing a β-pyridylalkylphosphine sulfide compound according to claim 2, characterized by, The inert atmosphere is a nitrogen atmosphere.

9. The method of producing a β-pyridylalkylphosphine sulfide compound according to claim 2, characterized by, The separation and purification method is as follows: the reaction solution is concentrated under reduced pressure to remove the organic solvent, column chromatography separation is carried out, and the mixed eluent of petroleum ether and ethyl acetate is used for flushing treatment, and the volume ratio of petroleum ether to ethyl acetate is 3:1-1:

1.

10. Use of the β-pyridylalkylphosphine sulfide compound according to claim 1 for the manufacture of an antitumor medicament, characterized in that, The antitumor drug is an anti-liver tumor drug.

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