Gamma-trifluoromethylpyridine compound as well as synthesis method and application thereof

Abstract

The invention belongs to the field of organic synthetic chemistry, and particularly relates to a gamma-trifluoromethylpyridine compound as well as a synthesis method and application thereof. According to the synthesis method of the gamma-trifluoromethylpyridine compound, a nitrogen center free radical mediated chain activation strategy is utilized, trifluoromethyl free radicals with high reaction activity are generated through controllable activation of sodium trifluoromethanesulfinate, the free radicals are used for carrying out addition on double bonds of allyl carboxylic ester, and the gamma-trifluoromethylpyridine compound is obtained. Then, an intramolecular synergistic 1, 2-acyloxy free radical migration mechanism is triggered, a thermodynamically stable three-level carbon free radical intermediate is generated, and then a gamma-CF3 pyridine skeleton is accurately constructed through directional capture of pyridinium salt. The gamma-trifluoropyridine compound prepared by the invention contains trifluoromethyl and pyridine groups, can be used for later modification of synthesis of fluorine-containing pyridine medicines, and has important significance in the aspects of exploration of candidate medicines and structural modification of fluorine-containing pyridine medicine molecules.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthetic chemistry, and in particular relates to a gamma-trifluoromethylpyridine compound, a synthesis method and an application thereof. Background Art

[0002] The trifluoromethyl group not only has strong electron-withdrawing properties and lipophilicity, but also possesses a stable C—F bond. Introducing a trifluoromethyl group into a compound molecule can significantly improve its stability, lipid solubility, and enhance its biological activity. Pyridine is a common aromatic heterocyclic compound with unique biological activity and physicochemical properties. Its rigid skeleton can optimize receptor binding conformation. In the fields of pharmaceuticals and functional materials, trifluoromethyl and pyridine groups have become key tools for improving the drugability of compounds and material performance. For example, patent document CN115925680A discloses a trifluoromethyl-containing pyridine compound, its preparation method, and its application. This method uses fluopyram as a lead compound and modifies its structure to design and synthesize a series of trifluoromethyl-containing pyridine compounds with fungicidal activity. This new trifluoromethyl-containing pyridine compound provides a foundation for the research of low-toxic, highly effective fungicides.

[0003] Patent document CN115925680A discloses a trifluoromethylpyridine derivative, its preparation method, and application. This method utilizes trifluoromethyl α,β-unsaturated imine to construct a trifluoromethylpyridine derivative. The trifluoromethylpyridine derivative emits blue fluorescence at wavelengths between 300 and 500 nm. The trifluoromethylpyridine derivative exhibits excellent optical properties and antibacterial activity, and is expected to be used in the fields of organic luminescent materials and pesticides, with broad application prospects.

[0004] However, while fluorinated pyridine compounds can enhance their drugability and material performance by enhancing metabolic stability, regulating lipid solubility and membrane permeability, and precisely controlling molecular electronic effects, the development of synthetic techniques for these fluorinated pyridine compounds remains significantly limited. Currently, mainstream synthetic strategies focus on the construction of β-CF3 pyridine. These methods often rely on pre-modified substrates such as 4-cyanopyridine, and their limited applicability severely restricts their application scenarios.

[0005] Therefore, researching and developing a green synthesis method for fluorinated pyridine compounds that does not require pre-activated substrates, has mild conditions, and has regional selectivity is not only an urgent need in the field of synthetic chemistry of fluorinated pyridine compounds, but also a key path to breaking through the bottleneck of optimizing drug active molecules, and has a profound impact on the development of the medical and materials fields. Summary of the Invention

[0006] In order to address the defects of the prior art, the present invention provides a method for synthesizing γ-trifluoromethylpyridine compounds with visible light catalysis and universal substrate applicability. Specifically, it provides a new method for efficiently synthesizing γ-trifluoromethylpyridine compounds (γ-CF3pyridine) through a 1,2-radical migration (1,2-RaM) strategy under visible light catalysis.

[0007] This invention utilizes a nitrogen-centered radical-mediated chain activation strategy, generating a highly reactive trifluoromethyl radical through controlled activation with sodium trifluoromethylsulfinate. This radical then adds to the double bond of the allyl carboxylate, triggering a cooperative intramolecular 1,2-acyloxy radical migration mechanism to generate a thermodynamically stable tertiary carbon radical intermediate. This is then precisely constructed through targeted capture of the pyridinium salt to form a γ-CF3 pyridine skeleton. This method is suitable for constructing functional molecules in the fields of medicinal chemistry and functional materials.

[0008] The specific technical solutions of the present invention are as follows:

[0009] The present invention provides a γ-trifluoromethylpyridine compound, which is shown in Formula III:

[0010]

[0011] Among them, R 1 is any of alkyl and aryl groups, R 2 、R 3 is an alkyl group, R 4 It is any one of methyl, aryl, and H.

[0012] Furthermore, the R 1 is any one of C1-C3 alkyl and aryl, R 2 、R 3 is a C1-C3 alkyl group, R 4 It is any one of methyl, aryl, and H.

[0013] In addition, the present invention provides a method for synthesizing γ-trifluoromethylpyridine compounds, comprising the following steps:

[0014] Allyl carboxylate, N-aminopyridinium salt, sodium trifluoromethanesulfinate, sodium acetate and tris(2,2'-bipyrazine)ruthenium di(hexafluoroborate) ([Ru(bpz)3][PF6]2) are mixed, and an organic solvent is added under an inert gas environment. The mixture is magnetically stirred under green light irradiation until the reaction is completed, and the mixture is concentrated under reduced pressure. The concentrated crude product is separated and purified by silica gel column chromatography to obtain a compound of formula III.

[0015] Furthermore, the allyl carboxylate is as shown in Formula I:

[0016]

[0017] Among them, R 1 is any one of C1-C3 alkyl and aryl, R 2 、R 3 It is a C1-C3 alkyl group.

[0018] Furthermore, the N-aminopyridinium salt is represented by Formula II:

[0019]

[0020] Among them, R 4 It is any one of methyl, aryl, and H.

[0021] Furthermore, the molar ratio of the allyl carboxylate, N-aminopyridinium salt and sodium trifluoromethanesulfinate is 0.1mmoL:0.2mmoL:0.15mmoL.

[0022] Furthermore, the molar ratio of sodium acetate to allyl carboxylate is 0.15mmoL:0.1mmoL.

[0023] Furthermore, the molar ratio of tris(2,2'-bipyrazine)ruthenium di(hexafluoroborate) salt ([Ru(bpz)3][PF6]2) to allyl carboxylate is 0.002mmoL:0.1mmoL.

[0024] Furthermore, the organic solvent is one of acetonitrile and 1,2-dichloroethane.

[0025] Furthermore, the conditions of the green light irradiation are: wavelength 525nm, light intensity 40 watts, and irradiation time 12 to 20 hours.

[0026] Furthermore, the reaction equation for the synthesis process of the γ-trifluoromethylpyridine compound is:

[0027]

[0028] In addition, the present invention also seeks to protect the use of the γ-trifluoromethylpyridine compound in the preparation of drugs for preventing or treating colorectal cancer.

[0029] This invention innovatively proposes a dynamic synergistic mechanism based on visible light catalysis and 1,2-radical migration, achieving efficient and precise construction of γ-trifluoromethyl pyridine through non-preactivated olefins. Different from the synthesis of β-trifluoromethyl-substituted pyridine, this method uses the directional addition of trifluoromethyl radicals to allyl carboxylates to trigger a synergistic migration mechanism to form a thermodynamically stable tertiary carbon radical intermediate, and realizes the construction of γ-CF3 pyridine through dynamic capture of pyridinium salts. Through the dynamic regulation of radical cascade reactions, this pathway has achieved for the first time the efficient synthesis of γ-trifluoromethyl-substituted pyridines without substrate preactivation and dual control of chemical selectivity and regioselectivity. What is particularly critical is that this strategy establishes a new paradigm for the green synthesis of heterocyclic compounds through light-driven cascade migration of radicals and directional activation of pyridine, opening up a multi-dimensional innovation space for the rational design of fluorine-containing bioisosteres.

[0030] Preliminary biological activity experiments have shown that the γ-trifluoromethylpyridine compounds prepared by the present invention have a certain inhibitory effect on colorectal cancer cells HCT-116, providing a new direction for the research and development of new drugs for colon cancer.

[0031] In summary, compared with the existing technology, the synthesis method of γ-trifluoromethylpyridine compounds provided by the present invention realizes for the first time the efficient synthesis of γ-trifluoromethyl-substituted pyridines without the need for substrate preactivation and dual control of chemical selectivity and regioselectivity. This not only provides an efficient tool for the construction of fluorinated pyridine libraries, but also opens up a new direction for the green synthesis of polysubstituted heterocycles. DETAILED DESCRIPTION

[0032] The present invention is further described below by describing specific embodiments, but this is not intended to limit the present invention. Those skilled in the art may make various modifications or improvements based on the basic concept of the present invention, but as long as they do not depart from the basic concept of the present invention, they are all within the scope of the present invention. The materials involved in the present invention can be obtained by commercial means or conventional technical means in the field.

[0033] Example 1. Preparation of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl benzoate (3a)

[0034] (1) Preparation steps:

[0035] To a 10 ml reaction tube were added 2-methylbut-3-ene-2-benzyl ester 1a (19.0 mg, 0.1 mmol, 1.0 equiv.), 1-(N-methyl-p-toluenesulfonylamino)pyridinium tetrafluoroborate 2a (70.0 mg, 0.2 mmol, 2.0 equiv.), sodium trifluoromethanesulfinate (0.15 mmol, 1.5 equiv.), sodium acetate (0.15 mmol, 1.5 equiv.), and [Ru(bpz)3][PF6]2 (0.002 mmol, 2 mol%). The reaction solution was protected by nitrogen and 1 ml of the organic solvent 1,2-dichloroethane was added. The reaction was carried out under irradiation with green light at a wavelength of 525 nm and an intensity of 40 W in an oil bath at 80°C with magnetic stirring for 16 hours. After the reaction, extraction was performed with ethyl acetate (3×25 mL). The combined organic phases were washed with saturated brine (1×30 mL), then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The concentrated crude product was separated and purified by silica gel column chromatography (eluent, petroleum ether:ethyl acetate as eluent = 3:1 v / v, Rf = 0.3 in 3:1 v / v petroleum ether / ethyl acetate) to obtain 27.6 mg of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl benzoate (γ-CF3 pyridine compound 3a) as a light yellow oil in a yield of 82%.

[0036] (2) The reaction equation is as follows:

[0037]

[0038] (3) 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl benzoate (γ-CF3 pyridine compound 3a) was characterized. The characterization results were as follows:

[0039] 1 H NMR (500MHz, CDCl3) δ8.59(d,J=5.2Hz,2H),8.03(d,J=6.7Hz,2H),7.58(t,J=7.5Hz,1H),7.46(t,J=7.7Hz,2H) ,7.35(d,J=6.4Hz,2H),5.84(d,J=9.1Hz,1H),2.32–2.25(m,1H),2.15–2.06(m,1H),1.43(s,3H),1.38(s,3H); 13 C{ 1 H}NMR(126MHz, CDCl3)δ165.46,153.78,150.27,133.52,129.80,129.51,128.66,125.96(q, 1 J C-F=277.1Hz),121.77,72.67(q, 3 J C-F =2.6Hz),42.41,35.08(q, 2 J C-F =28.5Hz),25.65,22.18; 19 F NMR(471MHz, CDCl3)δ-64.59(s); HRMS(ESI)Calcd for C 18 H 18 F3NO2:[M+H] + =338.1362.Found:338.1366.

[0040] Example 2, Preparation of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 4-(trifluoromethyl)benzoate (3b)

[0041] (1) Preparation steps:

[0042] To a 10 ml reaction tube were added 2-methylbut-3-eno-2-yl 4-(trifluoromethyl)benzyl ester 1b (25.8 mg, 0.1 mmol, 1.0 equiv.), 1-(N-methyl-p-toluenesulfonylamino)pyridinium tetrafluoroborate 2a (70.0 mg, 0.2 mmol, 2.0 equiv.), sodium trifluoromethanesulfinate (0.15 mmol, 1.5 equiv.), sodium acetate (0.15 mmol, 1.5 equiv.), and [Ru(bpz)3][PF6]2 (0.002 mmol, 2 mol%). The reaction solution was protected by nitrogen and 1 ml of the organic solvent 1,2-dichloroethane was added. The reaction was then irradiated with green light at a wavelength of 525 nm and an intensity of 40 W in an oil bath at 80°C with magnetic stirring for 16 hours. After the reaction, extraction was performed with ethyl acetate (3×25 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrated crude product was separated and purified by silica gel column chromatography (eluent, petroleum ether:ethyl acetate as eluent = 3:1 v / v, Rf = 0.3 in 3:1 v / v petroleum ether / ethyl acetate) to obtain 28.4 mg of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 4-(trifluoromethyl) benzoate (γ-CF3 pyridine compound 3b) as a light yellow oil in a yield of 70%.

[0043] (2) The reaction equation is as follows:

[0044]

[0045] (3) 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 4-(trifluoromethyl)benzoate (γ-CF3 pyridine compound 3b) was characterized. The characterization results were as follows:

[0046] 1 H NMR (600MHz, CDCl3) δ8.63(d,J=5.5Hz,2H),8.11(d,J=8.1Hz,2H),7.73(d,J=8.2Hz,2H),7.43(d,J= 5.7Hz,2H),5.86(d,J=11.7Hz,1H),2.38–2.29(m,1H),2.21–2.13(m,1H),1.46(s,3H),1.42(s,3H); 13 C{ 1 H}NMR(151MHz,CDCl3)δ164.24,155.23,149.02,135.12(q, 2 J C-F =33.0Hz),132.56,130.20,125.83(q, 1 J C-F =277.4Hz),125.79(q, 3 J C-F =3.7Hz),125.43(q, 1 J C-F =273.1Hz),122.20,73.31(q, 3 J C-F =2.7Hz),42.60,35.02(q, 2 J C-F =28.8Hz),25.17,22.53; 19 F NMR(565MHz, CDCl3)δ-63.23(s),-64.58(s); HRMS(ESI)Calcd for C 19 H 17 F6NO2:[M+H] + =406.1236.Found:406.1246.

[0047] Example 3, Preparation of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 3-chlorobenzoate (3c)

[0048] (1) Preparation steps:

[0049] To a 10 ml reaction tube were added 2-methylbutan-3-en-2-yl-3-chlorobenzoate 1c (22.5 mg, 0.1 mmol, 1.0 equiv.), 1-(N-methyl-p-toluenesulfonylamino)pyridinium tetrafluoroborate 2a (70.0 mg, 0.2 mmol, 2.0 equiv.), sodium trifluoromethanesulfinate (0.15 mmol, 1.5 equiv.), sodium acetate (0.15 mmol, 1.5 equiv.), and [Ru(bpz)3][PF6]2 (0.002 mmol, 2 mol%). The reaction solution was protected by nitrogen and 1 ml of the organic solvent 1,2-dichloroethane was added. The reaction was then irradiated with green light at a wavelength of 525 nm and an intensity of 40 W in an oil bath at 80°C with magnetic stirring for 16 hours. After the reaction, extraction was performed with ethyl acetate (3×25 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrated crude product was separated and purified by silica gel column chromatography (eluent, petroleum ether:ethyl acetate as eluent = 3:1 v / v, Rf = 0.3 in 3:1 v / v petroleum ether / ethyl acetate) to obtain 26.6 mg of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 3-chlorobenzoate (γ-CF3 pyridine compound 3c) as a yellow solid with mp = 70.0-70.8°C and a yield of 72%.

[0050] (2) The reaction equation is as follows:

[0051]

[0052] (3) 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 3-chlorobenzoate (γ-CF3 pyridine compound 3c) was characterized. The characterization results were as follows:

[0053] 1 H NMR (500MHz, CDCl3) δ8.61(d,J=5.2Hz,2H),7.98(t,J=1.9Hz,1H),7.90(dt,J=7.8,1.4Hz,1H),7.57(ddd,J=8.0,2.2,1.1Hz,1H),7 .41(t,J=7.9Hz,1H),7.38(d,J=6.3Hz,2H),5.84(d,J=11.7Hz,1H),2.35–2.28(m,1H),2.18–2.08(m,1H),1.45(s,3H),1.39(s,3H); 13 C{ 1H}NMR(126MHz, CDCl3)164.29,154.22,149.90,134.89,133.64,131.19,130.06,129.81,127.98,125.89(q, 1 J C-F =277.3Hz),121.90,73.19(q, 3 J C-F =2.6Hz),42.48,35.04(q, 2 J C-F =28.7Hz),25.50,22.25; 19 F NMR(471MHz, CDCl3)δ-64.61(s); HRMS(ESI)Calcd for C 18 H 17 ClF3NO2:[M+H] + =372.0973.Found:372.0983.

[0054] Example 4. Preparation of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 3,4-dimethoxybenzoate (3d)

[0055] (1) Preparation steps:

[0056] To a 10 mL reaction tube were added 2-methylbut-3-en-2-yl 3,4-dimethoxybenzoate 1d (25.0 mg, 0.1 mmol, 1.0 equiv.), 1-(N-methyl-p-toluenesulfonylamino)pyridinium tetrafluoroborate 2a (70.0 mg, 0.2 mmol, 2.0 equiv.), sodium trifluoromethanesulfinate (0.15 mmol, 1.5 equiv.), sodium acetate (0.15 mmol, 1.5 equiv.), and [Ru(bpz)3][PF6]2 (0.002 mmol, 2 mol%). The reaction solution was protected by nitrogen and 1 mL of the organic solvent 1,2-dichloroethane was added. The reaction was then irradiated with green light at a wavelength of 525 nm and an intensity of 40 W in an oil bath at 80°C with magnetic stirring for 16 hours. After the reaction, extraction was performed with ethyl acetate (3×25 mL). The combined organic phases were washed with saturated brine (1×30 mL), then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The concentrated crude product was separated and purified by silica gel column chromatography (eluent, petroleum ether:ethyl acetate as eluent = 3:1 v / v, Rf = 0.2 in 3:1 v / v petroleum ether / ethyl acetate) to obtain 25.7 mg of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 3,4-dimethoxybenzoate (γ-CF3 pyridine compound 3d) as a yellow solid with mp = 100.3-101.0°C and a yield of 65%.

[0057] (2) The reaction equation is as follows:

[0058]

[0059] (3) 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 3,4-dimethoxybenzoate (γ-CF3 pyridine compound 3d) was characterized. The characterization results were as follows:

[0060] 1 H NMR (500MHz, CDCl3) δ8.62(d,J=5.3Hz,2H),7.64(dd,J=8.4,2.0Hz,1H),7.50(d,J=2.0Hz,1H),7.47(d,J=5.2Hz,2H),6.90(d,J =8.4Hz,1H),5.80(d,J=10.1Hz,1H),3.93(s,3H),3.92(s,3H),2.31–2.24(m,1H),2.19–2.12(m,1H),1.44(s,3H),1.41(s,3H); 13 C{ 1H}NMR(126MHz, CDCl3)δ165.11,156.07,153.63,148.96,148.40,125.89(q, 1 J C-F =277.4Hz),123.71,122.50,121.68,112.34,110.49,72.32(q, 3 J C-F =2.2Hz),56.19,56.12,42.74,35.09(q, 2 J C-F =28.6Hz),25.15,22.75; 19 F NMR(471MHz, CDCl3)δ-64.48(s); HRMS(ESI)Calcd for C 20 H 22 F3NO4:[M+H] + =398.1574.Found:398.1590.

[0061] Example 5, Preparation of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 5-chlorothiophene-2-carboxylate (3e)

[0062] (1) Preparation steps:

[0063] To a 10 ml reaction tube were added 2-methylbut-3-en-2-yl 5-chlorothiophene-2-carboxylate 1e (23.1 mg, 0.1 mmol, 1.0 equiv.), 1-(N-methyl-p-toluenesulfonylamino)pyridinium tetrafluoroborate 2a (70.0 mg, 0.2 mmol, 2.0 equiv.), sodium trifluoromethanesulfinate (0.15 mmol, 1.5 equiv.), sodium acetate (0.15 mmol, 1.5 equiv.), and [Ru(bpz)3][PF6]2 (0.002 mmol, 2 mol%). The reaction solution was protected by nitrogen and 1 ml of the organic solvent 1,2-dichloroethane was added. The reaction was then irradiated with green light at a wavelength of 525 nm and an intensity of 40 W in an oil bath at 80°C with magnetic stirring for 16 hours. After the reaction, extraction was performed with ethyl acetate (3×25 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrated crude product was separated and purified by silica gel column chromatography (eluent, petroleum ether:ethyl acetate as eluent = 2:1 v / v, Rf = 0.3 in 2:1 v / v petroleum ether / ethyl acetate) to obtain 17.3 mg of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 5-chlorothiophene-2-carboxylate (γ-CF3 pyridine compound 3e) as a light yellow oil in a yield of 46%.

[0064] (2) The reaction equation is as follows:

[0065]

[0066] (3) 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 5-chlorothiophene-2-carboxylate (γ-CF3 pyridine compound 3e) was characterized. The characterization results were as follows:

[0067] 1 H NMR (500MHz, CDCl3) δ8.65(d,J=4.6Hz,2H),7.62(d,J=4.0Hz,1H),7.44(d,J=3.5Hz,2H),6 .97(d,J=4.0Hz,1H),5.71(d,J=10.0Hz,1H),2.17–2.07(m,2H),1.43(s,3H),1.41(s,3H); 13 C{ 1 H}NMR(126MHz, CDCl3)δ159.91,155.43,149.02,138.46,134.11,130.43,127.77,125.78(q, 1 J C-F =277.1Hz),122.38,73.16(q,3 J C-F =2.8Hz),42.65,35.05(q, 2 J C-F =28.9Hz),25.12,22.75; 19 F NMR(471MHz, CDCl3)δ-64.60(s); HRMS(ESI)Calcdfor C 16 H 15 ClF3NO2S:[M+H] + =378.0537.Found:378.0541.

[0068] Example 6, Preparation of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 2-(4-fluorophenyl)acetate (3f)

[0069] (1) Preparation steps:

[0070] To a 10 ml reaction tube were added 2-methylbut-3-en-2-yl 2-(4-fluorophenyl)acetate 1f (22.2 mg, 0.1 mmol, 1.0 equiv.), 1-(N-methyl-p-toluenesulfonylamino)pyridinium tetrafluoroborate 2a (70.0 mg, 0.2 mmol, 2.0 equiv.), sodium trifluoromethanesulfinate (0.15 mmol, 1.5 equiv.), sodium acetate (0.15 mmol, 1.5 equiv.), and [Ru(bpz)3][PF6]2 (0.002 mmol, 2 mol%). The reaction solution was protected by nitrogen and 1 ml of the organic solvent 1,2-dichloroethane was added. The reaction was then irradiated with green light at a wavelength of 525 nm and an intensity of 40 W in an oil bath at 80°C with magnetic stirring for 16 hours. After the reaction, extraction was performed with ethyl acetate (3×25 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrated crude product was separated and purified by silica gel column chromatography (eluent, petroleum ether:ethyl acetate as eluent = 3:1 v / v, Rf = 0.3 in 3:1 v / v petroleum ether / ethyl acetate) to obtain 27.0 mg of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 2-(4-fluorophenyl) acetate (γ-CF3 pyridine compound 3f) as a light yellow oil in a yield of 73%.

[0071] (2) The reaction equation is as follows:

[0072]

[0073] (3) 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 2-(4-fluorophenyl) acetate (γ-CF3 pyridine compound 3f) was characterized. The characterization results were as follows:

[0074] 1 H NMR (600MHz, CDCl3) δ8.55 (s, 2H), 7.21–7.17 (m, 4H), 7.03 (t, J = 8.6Hz, 2H), 5.56 (d,J=9.2Hz,1H),3.61–3.55(m,2H),2.13–2.01(m,2H),1.25(s,3H),1.24(s,3H); 13 C{ 1 H}NMR(151MHz,CDCl3)δ169.99,162.26(d, 1 J C-F =246.2Hz),155.11,149.14,131.09(d, 3 J C-F =7.9Hz),129.25(d, 4 J C-F =3.2Hz),125.87(q, 1 J C-F =277.3Hz),122.18,115.71(d, 2 J C-F =21.5Hz),72.51(q, 3 J C-F =2.7Hz),42.23,40.65,34.92(q, 2 J C-F =28.6Hz),24.59,22.88; 19 F NMR(565MHz, CDCl3)δ-64.63,-115.08(s); HRMS(ESI)Calcd for C 19 H 19 F4NO2:[M+H] + =370.1425.Found:370.1433.

[0075] Example 7, Preparation of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-ylcyclopropanecarboxylate (3 g)

[0076] (1) Preparation steps:

[0077] To a 10 ml reaction tube were added 1 g (22.2 mg, 0.1 mmol, 1.0 equiv.) of 2-methylbut-3-en-2-ylcyclopropanecarboxylate, 1-(N-methyl-p-toluenesulfonylamino)pyridinium tetrafluoroborate 2a (70.0 mg, 0.2 mmol, 2.0 equiv.), sodium trifluoromethanesulfinate (0.15 mmol, 1.5 equiv.), sodium acetate (0.15 mmol, 1.5 equiv.), and [Ru(bpz)3][PF6]2 (0.002 mmol, 2 mol%). The reaction solution was protected with nitrogen and 1 ml of the organic solvent 1,2-dichloroethane was added. The reaction was then irradiated with green light at a wavelength of 525 nm and an intensity of 40 W in an oil bath at 80°C with magnetic stirring for 16 hours. After the reaction, extraction was performed with ethyl acetate (3×25 mL), and the combined organic phases were washed with saturated brine (1×30 mL), then dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrated crude product was separated and purified by silica gel column chromatography (eluent, petroleum ether: ethyl acetate as eluent = 3:1 v / v, Rf = 0.3 in 3:1 v / v petroleum ether / ethyl acetate) to obtain 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-ylcyclopropanecarboxylate (γ-CF3 pyridine compound 3 g) 21.0 mg as a light yellow oil with a yield of 70%.

[0078] (2) The reaction equation is as follows:

[0079]

[0080] (3) Characterization of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-ylcyclopropanecarboxylate (γ-CF3 pyridine compound 3g) was performed. The characterization results were as follows:

[0081] 1 H NMR (500MHz, CDCl3) δ8.57(d,J=6.3Hz,2H),7.30(d,J=6.4Hz,2H),5.57(d,J=10.2Hz,1H),2.19–2.07(m,1 H),2.02–1.93(m,1H),1.63–1.58(m,1H),1.34(s,3H),1.31(s,3H),1.01–0.92(m,2H),0.88–0.85(m,2H); 13 C{ 1 H}NMR(126MHz,CDCl3)δ173.74,154.18,150.03,125.98(q, 1 J C-F =277.1Hz),121.81,71.89(q, 3 JC-F =2.3Hz),42.19,34.94(q, 2 J C-F =28.5Hz),25.29,22.18,12.85,8.56,8.46; 19 F NMR(471MHz, CDCl3)δ-64.70(s); HRMS(ESI)Calcd for C 15 H 18 F3NO2:[M+H] + =302.1362.Found:302.1376.

[0082] Example 8, Preparation of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl-4-chlorobutyrate (3h)

[0083] (1) Preparation steps:

[0084] To a 10 ml reaction tube were added 2-methylbut-3-eno-2-yl 4-chlorobutanoate 1h (19.1 mg, 0.1 mmol, 1.0 equiv.), 1-(N-methyl-p-toluenesulfonylamino)pyridinium tetrafluoroborate 2a (70.0 mg, 0.2 mmol, 2.0 equiv.), sodium trifluoromethanesulfinate (0.15 mmol, 1.5 equiv.), sodium acetate (0.15 mmol, 1.5 equiv.), and [Ru(bpz)3][PF6]2 (0.002 mmol, 2 mol%). The reaction solution was protected by nitrogen and 1 ml of the organic solvent 1,2-dichloroethane was added. The reaction was then irradiated with green light at a wavelength of 525 nm and an intensity of 40 W in an oil bath at 80°C with magnetic stirring for 16 hours. After the reaction, extraction was performed with ethyl acetate (3×25 mL). The combined organic phases were washed with saturated brine (1×30 mL), then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The concentrated crude product was separated and purified by silica gel column chromatography (eluent, petroleum ether:ethyl acetate as eluent = 3:1 v / v, Rf = 0.3 in 3:1 v / v petroleum ether / ethyl acetate) to obtain 24.3 mg of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl-4-chlorobutyrate (γ-CF3 pyridine compound 3h) as a light yellow oil with a yield of 72%.

[0085] (2) The reaction equation is as follows:

[0086]

[0087] (3) 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl-4-chlorobutyrate (γ-CF3 pyridine compound 3h) was characterized. The characterization results were as follows:

[0088] 1 H NMR (500MHz, CDCl3) δ8.58(d,J=5.0Hz,2H),7.30(d,J=4.7Hz,2H),5.58(d,J=9.0Hz,1H),3.57–3. 50(m,2H),2.49(t,J=7.2Hz,2H),2.19–2.10(m,1H),2.06–1.99(m,3H),1.34(s,3H),1.31(s,3H); 13 C{ 1 H}NMR(126MHz,CDCl3)δ171.49,154.09,150.07,125.96(q, 1 J C-F =277.1Hz),121.76,72.25(q, 3 J C-F =2.7Hz),43.90,42.02,34.88(q, 2 J C-F =28.6Hz)31.04,27.44,24.97,22.43; 19 F NMR(471MHz, CDCl3)δ-64.68(s); HRMS(ESI)Calcdfor C 15 H 19 ClF3NO2:[M+H] + =338.1129.Found:338.1143.

[0089] Example 9, Preparation of 3,3,3-trifluoro-1-(1-(pyridin-4-yl)cyclobutyl)propyl benzoate (3i)

[0090] (1) Preparation steps:

[0091] In a 10 ml reaction tube, 1-vinylbenzoic acid cyclobutyl ester 1i (20.2 mg, 0.1 mmol, 1.0 equiv.), 1-(N-methyl-p-toluenesulfonylamino)pyridinium tetrafluoroborate 2a (70.0 mg, 0.2 mmol, 2.0 equiv.), sodium trifluoromethanesulfinate (0.15 mmol, 1.5 equiv.), sodium acetate (0.15 mmol, 1.5 equiv.) and [Ru(bpz)3][PF6]2 were added.

[0092] The reaction mixture was protected by nitrogen and 1 mL of 1,2-dichloroethane was added as an organic solvent. The reaction was stirred magnetically in an oil bath at 80°C for 16 hours under irradiation with green light at a wavelength of 525 nm and an intensity of 40 W. After the reaction, the mixture was extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with saturated brine (1 × 30 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrated crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 3:1 v / v, Rf = 0.3 in 3:1 v / v petroleum ether / ethyl acetate) to obtain 19.1 mg of 3,3,3-trifluoro-1-(1-(pyridin-4-yl)cyclobutyl)propyl benzoate (γ-CF3 pyridine compound 3i) as a light yellow oil in a 55% yield.

[0093] (2) The reaction equation is as follows:

[0094]

[0095] (3) 3,3,3-trifluoro-1-(1-(pyridin-4-yl)cyclobutyl)propyl benzoate (γ-CF3 pyridine compound 3i) was characterized. The characterization results were as follows:

[0096] 1 H NMR (600MHz, CDCl3) δ8.50(d,J=4.9Hz,2H),8.09(d,J=6.9Hz,2H),7.66–7.63(m,1H),7.50(t,J=7.8Hz,2H),7.14(d,J =5.5Hz,2H),5.20(t,J=7.2Hz,1H),2.86–2.79(m,2H),2.69(t,J=7.8Hz,2H),2.44(t,J=7.7Hz,2H),1.89–1.84(m,2H); 13 C{ 1 H}NMR(151MHz, CDCl3)δ164.02,153.05,151.48,149.27,134.06,130.18,128.89,125.88(q, 1 J C-F =276.5Hz),124.24,105.92(q, 3 J C-F =3.7Hz),34.40,33.02,31.02(q, 2 J C-F =30.6Hz),26.95; 19F NMR(565MHz, CDCl3)δ-66.20(s); HRMS(ESI)Calcd for C 19 H 18 F3NO2:[M+H] + =350.1362.Found:350.1367.

[0097] Example 10, Preparation of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 4-([1,1'-biphenyl]-4-yl)-4-oxobutyrate (3j)

[0098] (1) Preparation steps:

[0099] To a 10 mL reaction tube were added 2-methyl-3-en-2-yl-4-([1,1'-biphenyl]-4-yl)-4-oxobutanoate 1j (32.2 mg, 0.1 mmol, 1.0 equiv.), 1-(N-methyl-p-toluenesulfonylamino)pyridinium tetrafluoroborate 2a (70.0 mg, 0.2 mmol, 2.0 equiv.), sodium trifluoromethanesulfinate (0.15 mmol, 1.5 equiv.), sodium acetate (0.15 mmol, 1.5 equiv.), and [Ru(bpz)3][PF6]2 (0.002 mmol, 2 mol%). The reaction mixture was protected by nitrogen and 1 mL of 1,2-dichloroethane was added. The reaction was then stirred magnetically in an oil bath at 80°C for 16 hours under irradiation with 525 nm green light at 40 W. After the reaction, extraction was performed with ethyl acetate (3×25 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrated crude product was separated and purified by silica gel column chromatography (eluent, petroleum ether:ethyl acetate as eluent = 3:1 v / v, Rf = 0.3 in 2:1 v / v petroleum ether / ethyl acetate) to obtain 37.4 mg of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 4-([1,1'-biphenyl]-4-yl)-4-oxobutyrate (γ-CF3 pyridine compound 3j) as a yellow solid with mp = 98.7-99.5°C and a yield of 80%.

[0100] (2) The reaction equation is as follows:

[0101]

[0102] (3) 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 4-([1,1'-biphenyl]-4-yl)-4-oxobutyrate (γ-CF3 pyridine compound 3j) was characterized. The characterization results were as follows:

[0103] 1 H NMR (500MHz, CDCl3) δ8.58(d,J=5.2Hz,2H),8.05(d,J=8.4Hz,2H),7.70(d,J=8.3Hz,2H ),7.63(d,J=7.6Hz,2H),7.47(t,J=7.6Hz,2H),7.39(t,J=7.3Hz,1H),7.35(d,J=5.8Hz, 2H),5.60(dd,J=10.3,1.3Hz,1H),3.42–3.36(m,1H),3.29–3.23(m,1H),2.87–2.81(m, 1H),2.77–2.71(m,1H),2.19–2.10(m,1H),2.05–1.97(m,1H),1.38(s,3H),1.37(s,3H); 13 C{ 1 H}NMR(126MHz, CDCl3)δ197.46,171.90,154.55,149.61,146.11,139.87,135.21,129.07,128.73,128.39,127.41,127.37,125.99(q, 1 J C-F =277.3Hz),122.02,72.38(q, 3 J C-F =2.6Hz),42.21,34.92(q, 2 J C-F =28.5Hz),33.29,28.27,25.26,22.38; 19 FNMR(471MHz,CDCl3)δ-64.61(s); HRMS(ESI)Calcd for C 27 H 26 F3NO3:[M+H] + =470.1938.Found:470.1949.

[0104] Example 11. Preparation of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1h-indol-3-yl) acetate (3k)

[0105] (1) Preparation steps:

[0106] In a 10 ml reaction tube, 2-methyl-3-en-2-yl-2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetic acid 1k (42.6 mg, 0.1 mmol, 1.0 equiv.), 1-(N-methyl-p-toluenesulfonylamino)pyridinium tetrafluoroborate 2a (70.0 mg, 0.2 mmol, 2.0 equiv.), sodium trifluoromethanesulfinate (0.15 mmol, 1.5 equiv.), sodium acetate (0.15 mmol, 1.5 equiv.) and

[0107] [Ru(bpz)3][PF6]2 (0.002 mmol, 2 mol%) was added to the reaction mixture under nitrogen atmosphere and 1 ml of the organic solvent 1,2-dichloroethane was added. The reaction was irradiated with green light at a wavelength of 525 nm and an intensity of 40 watts in an oil bath at 80°C with magnetic stirring for 16 hours. After the reaction, extraction was performed with ethyl acetate (3×25 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The concentrated crude product was separated and purified by silica gel column chromatography (eluent, petroleum ether:ethyl acetate as eluent = 3:1 v / v, Rf = 0.3 in 2:1 v / v petroleum ether / ethyl acetate) to obtain 34.4 mg of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1h-indol-3-yl) acetate (γ-CF3 pyridine compound 3k) as a light yellow oil in a yield of 60%.

[0108] (2) The reaction equation is as follows:

[0109]

[0110] (3) 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1h-indol-3-yl) acetate (γ-CF3 pyridine compound 3k) was characterized. The characterization results were as follows:

[0111] 1H NMR (500MHz, CDCl3) δ8.40(d,J=5.4Hz,2H),7.66(d,J=8.5Hz,2H),7.47(d,J =8.5Hz,2H),7.15(d,J=6.4Hz,2H),6.93(d,J=9.0Hz,1H),6.88(d,J=2.5Hz, 1H),6.73(dd,J=9.0,2.5Hz,1H),5.56(dd,J=8.0,3.7Hz,1H),3.83(s,3H),3 .70–3.62(m,2H),2.33(s,3H),2.11–2.04(m,2H),1.26(s,3H),1.21(s,3H); 13 C{ 1 H}NMR(126MHz, CDCl3)δ169.30,168.50,156.29,147.74,139.69,136.10,133.74,131.41,130.92,130.51,129.50,129.34,125.89(q, 1 J C-F =277.4Hz),122.36,115.20,112.02,111.83,101.38,72.54(q, 3 J C-F =2.8Hz),55.88,42.36,35.01(q, 2 J C-F = 28.6 Hz), 30.29, 24.05, 23.66, 13.27; 19 FNMR (471 MHz, CDCl3) δ - 64.47 (s); HRMS(ESI)Calcd for C 30 H 28 ClF3N2O4:[M+H] + =573.1762.Found:573.1772.

[0112] Example 12, Preparation of 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 2-(3-cyano-4-isobutylphenyl)-4-methylthiazole-5-carboxylate (31)

[0113] (1) Preparation steps:

[0114] To a 10 ml reaction tube were added 2-methylbut-3-en-2-yl-2-(3-cyano-4-isobutylphenyl)-4-methylthiazole-5-carboxylate 11 (38.4 mg, 0.1 mmol, 1.0 equiv.), 1-(N-methyl-p-toluenesulfonylamino)pyridinium tetrafluoroborate 2a (70.0 mg, 0.2 mmol, 2.0 equiv.), sodium trifluoromethanesulfinate (0.15 mmol, 1.5 equiv.), sodium acetate (0.15 mmol, 1.5 equiv.), and [Ru(bpz)3][PF6]2 (0.002 mmol, 2 mol%). The reaction solution was protected with nitrogen and 1 ml of the organic solvent 1,2-dichloroethane was added. The reaction was then irradiated with green light at a wavelength of 525 nm and an intensity of 40 W in an oil bath at 80°C with magnetic stirring for 16 hours. After the reaction, extraction was performed with ethyl acetate (3×25 mL). The combined organic phases were washed with saturated brine (1×30 mL), then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The concentrated crude product was separated and purified by silica gel column chromatography (eluent, petroleum ether:ethyl acetate as eluent = 3:1 v / v, Rf = 0.3 in 2:1 v / v petroleum ether / ethyl acetate) to obtain 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 2-(3-cyano-4-isobutylphenyl)-4-methylthiazole-5-carboxylate (γ-CF3 pyridine compound 3l) 28.2 mg as a light yellow oil in a yield of 53%.

[0115] (2) The reaction equation is as follows:

[0116]

[0117] (3) 1,1,1-trifluoro-4-methyl-4-(pyridin-4-yl)pentan-3-yl 2-(3-cyano-4-isobutylphenyl)-4-methylthiazole-5-carboxylate (γ-CF3 pyridine compound 31) was characterized. The characterization results were as follows:

[0118] 1 H NMR (500MHz, CDCl3) δ8.63(d,J=5.2Hz,2H),8.18(d,J=2.3Hz,1H),8.11(dd,J=8.8,2.3Hz,1H),7.40(d,J=6.4Hz,2H),7.02(d,J=8.8Hz,1 H),5.75(dd,J=10.2,1.3Hz,1H),3.90(d,J=6.5Hz,2H),2.75(s,3H),2.26–2.10(m,3H),1.45(s,3H),1.41(s,3H),1.09(d,J=6.7Hz,6H); 13 C{1 H}NMR(126MHz, CDCl3)δ167.99,162.81,162.67,160.75,154.60,149.59,132.79,132.35,125.92,125.85(q, 1 J C-F =276.9Hz),122.06,120.34,115.47,112.82,103.18,75.88,73.06,42.46,35.05(q, 2 J C-F =28.5Hz),28.29,25.33,22.47,19.17,17.69; 19 F NMR(471MHz, CDCl3)δ-64.53(s); HRMS(ESI)Calcd forC 27 H 28 F3N3O3S:[M+H] + =532.1876.Found:532.1891.

[0119] Example 13, Preparation of 1,1,1-trifluoro-4-methyl-4-(2-methylpyridin-4-yl)pentan-3-ylbenzoate (3m)

[0120] (1) Preparation steps:

[0121] To a 10 ml reaction tube were added 2-methylbut-3-ene-2-benzyl ester 1a (19.0 mg, 0.1 mmol, 1.0 equiv.), 1-(N-methyl-p-toluenesulfonylamino)-2-methylpyridinium tetrafluoroborate 2b (72.8 mg, 0.2 mmol, 2.0 equiv.), sodium trifluoromethanesulfinate (0.15 mmol, 1.5 equiv.), sodium acetate (0.15 mmol, 1.5 equiv.), and [Ru(bpz)3][PF6]2 (0.002 mmol, 2 mol%). The reaction solution was protected by nitrogen and 1 ml of the organic solvent 1,2-dichloroethane was added. The reaction was carried out under irradiation with green light at a wavelength of 525 nm and an intensity of 40 W in an oil bath at 80°C with magnetic stirring for 16 hours. After the reaction, extraction was performed with ethyl acetate (3×25 mL). The combined organic phases were washed with saturated brine (1×30 mL), then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The concentrated crude product was separated and purified by silica gel column chromatography (eluent, petroleum ether:ethyl acetate as eluent = 3:1 v / v, Rf = 0.3 in 3:1 v / v petroleum ether / ethyl acetate) to obtain 24.9 mg of 1,1,1-trifluoro-4-methyl-4-(2-methylpyridin-4-yl)pentan-3-yl benzoate (γ-CF3 pyridine compound 3m) as a light yellow oil in a yield of 71%.

[0122] (2) The reaction equation is as follows:

[0123]

[0124] (3) 1,1,1-trifluoro-4-methyl-4-(2-methylpyridin-4-yl)pentan-3-yl benzoate (γ-CF3 pyridine compound 3m) was characterized. The characterization results were as follows:

[0125] 1 H NMR (600MHz, CDCl3) δ8.49(d,J=5.4Hz,1H),8.03(dd,J=8.2,1.4Hz,2H),7.60(t,J=7.4Hz,1H),7.47(t,J=7.8Hz,2H),7.27(d,J=1.7Hz ,1H),7.24(dd,J=5.6,1.8Hz,1H),5.83(d,J=10.7Hz,1H),2.62(s,3H),2.35–2.26(m,1H),2.16–2.09(m,1H),1.44(s,3H),1.38(s,3H); 13 C{ 1H}NMR(151MHz, CDCl3)δ165.44,158.32,155.62,148.31,133.61,129.83,129.46,128.71,125.95(q, 1 J C-F =277.3Hz),121.92,119.31,72.64(q, 3 J C-F =2.7Hz),42.58,35.10(q, 2 J C-F =28.7Hz),25.58,24.04,22.24; 19 F NMR(565MHz, CDCl3)δ-64.56(s); HRMS(ESI)Calcd for C 19 H 20 F3NO2:[M+H] + =352.1519.Found:352.1530.

[0126] Example 14, Preparation of 4-(2-(2,4-difluorophenyl)pyridin-4-yl)-1,1,1-trifluoro-4-methylpentan-3-ylbenzoate (3n)

[0127] (1) Preparation steps:

[0128] To a 10 mL reaction tube were added 2-methylbut-3-en-2-ylbenzyl ester 1a (19.0 mg, 0.1 mmol, 1.0 equiv.), 1-(N-methyl-p-toluenesulfonylamino)-2-(2,4-fluorophenyl)pyridinium tetrafluoroborate 2c (92.4 mg, 0.2 mmol, 2.0 equiv.), sodium trifluoromethanesulfinate (0.15 mmol, 1.5 equiv.), sodium acetate (0.15 mmol, 1.5 equiv.), and [Ru(bpz)3][PF6]2 (0.002 mmol, 2 mol%). The reaction solution was protected by nitrogen and 1 mL of 1,2-dichloroethane was added as an organic solvent. The reaction was stirred magnetically in an oil bath at 80°C for 16 hours under irradiation with 525 nm green light at 40 W. After the reaction, extraction was performed with ethyl acetate (3×25 mL). The combined organic phases were washed with saturated brine (1×30 mL), then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The concentrated crude product was separated and purified by silica gel column chromatography (eluent, petroleum ether:ethyl acetate as eluent = 8:1 v / v, Rf = 0.6 in 4:1 v / v petroleum ether / ethyl acetate) to obtain 4-(2-(2,4-difluorophenyl)pyridin-4-yl)-1,1,1-trifluoro-4-methylpentan-3-yl benzoate (γ-CF3 pyridine compound 3n) 26.8 mg as light yellow crystals, mp = 109.8-110.5°C, and a yield of 60%.

[0129] (2) The reaction equation is as follows:

[0130]

[0131] (3) p-4-(2-(2,4-difluorophenyl)pyridin-4-yl)-1,1,1-trifluoro-4-methylpentan-3-ylbenzoate (γ-CF3 pyridine compound 3n) δ 8.70 (d, J = 5.3 Hz, 1H), 8.05 (dd, J = 8.3, 1.4 Hz, 2H), 7.98–7.94 (m, 1H), 7.81 (s, 1H), 7.61–7.58 (m, 1H), 7 .46(t,J=7.8Hz,2H),7.34(dd,J=5.3,1.9Hz,1H),7.03–6.99(m,1H),6.95–6.91(m,1H),5. 89(dd,J=10.2,1.3Hz,1H),2.36–2.28(m,1H),2.22–2.14(m,1H),1.48(s,3H),1.44(s,3H); 13 C{ 1 H}NMR(151MHz,CDCl3)δ165.53,163.44(dd, 1 JC-F =251.1, 3 J C-F =12.1Hz),160.64(dd, 1 J C-F =252.2, 3 J C-F =12.0Hz),154.32,153.29(d, 4 J C-F =2.7Hz),150.24,133.54,132.41(dd, 3 J C-F =9.7, 3 J C-F =4.3Hz),129.87,129.53,128.66,126.00(q, 1 J C-F =277.4Hz),123.86(dd, 2 J C-F =11.6, 4 J C-F =3.9Hz),122.41(d, 3 J C-F =9.2Hz),120.56,112.10(dd, 2 J C-F =21.2, 4 J C-F =3.6Hz),104.54(dd, 2 J C-F =26.9, 2 J C-F =25.6Hz),72.78(q, 3 J C-F =2.7Hz),42.61,35.19(q, 2 J C-F =28.7Hz),25.77,22.48; 19 F NMR(565MHz, CDCl3)δ-64.57(s),-108.87(s),-112.84(s); HRMS(ESI)Calcd for C 24 H 20 F5NO2:[M+H] + =450.1487.Found:450.1495.

[0132] Example 15. Preparation of 1,1,1-trifluoro-4-methyl-4-(2-(thiophen-2-yl)pyridin-4-yl)pentan-3-ylbenzoate (3o)

[0133] (1) Preparation steps:

[0134] To a 10 ml reaction tube were added 2-methylbut-3-ene-2-benzyl ester 1a (19.0 mg, 0.1 mmol, 1.0 equiv.), 1-(N-methyl-p-toluenesulfonylamino)-2-(thiophen-2-yl)pyridinium tetrafluoroborate 2d (86.5 mg, 0.2 mmol, 2.0 equiv.), sodium trifluoromethanesulfinate (0.15 mmol, 1.5 equiv.), sodium acetate (0.15 mmol, 1.5 equiv.), and [Ru(bpz)3][PF6]2 (0.002 mmol, 2 mol%). The reaction solution was protected with nitrogen and 1 ml of the organic solvent 1,2-dichloroethane was added. The reaction was then irradiated with green light at a wavelength of 525 nm and an intensity of 40 W in an oil bath at 80°C with magnetic stirring for 16 hours. After the reaction, extraction was performed with ethyl acetate (3×25 mL). The combined organic phases were washed with saturated brine (1×30 mL), then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The concentrated crude product was separated and purified by silica gel column chromatography (eluent, petroleum ether:ethyl acetate as eluent = 10:1 v / v, Rf = 0.4 in 8:1 v / v petroleum ether / ethyl acetate) to obtain 30.2 mg of 1,1,1-trifluoro-4-methyl-4-(2-(thiophen-2-yl)pyridin-4-yl)pentan-3-yl benzoate (γ-CF3 pyridine compound 3o) as a light yellow oil in a yield of 72%.

[0135] (2) The reaction equation is as follows:

[0136]

[0137] (3) 1,1,1-trifluoro-4-methyl-4-(2-(thien-2-yl)pyridin-4-yl)pentan-3-yl benzoate (γ-CF3 pyridine compound 3o) was characterized. The characterization results were as follows:

[0138] 1 H NMR(600MHz, CDCl3)δ8.56(d,J=4.8Hz,1H),8.12(dd,J=8.3,1.4Hz,2H),7.68(td,J=7.7,1.7Hz,1H),7.64–7.63(m,1H),7.59(tt,J=7.1,1.3Hz,1H), 7.49–7.47(m,3H),7.15(ddd,J=7.4,4.8,1.2Hz,1H),7.00(d,J=3.7Hz,1H) ,5.77(dd,J=8.1,3.6Hz,1H),2.42–2.35(m,2H),1.51(s,3H),1.49(s,3H); 13 C{1 H}NMR(151MHz, CDCl3)δ165.64,152.47,151.61,149.64,143.42,136.88,133.41,129.98,129.73,128.63,126.23(q, 1 J C-F =277.2Hz),125.44,124.57,122.06,118.67,73.47(q, 3 J C-F =2.6Hz),42.08,35.21(q, 2 J C-F =28.4Hz),27.64,24.57; 19 F NMR(471MHz, CDCl3)δ-64.33(s); HRMS(ESI)Calcd forC 22 H 20 F3NO2S:[M+H] + =420.1240.Found:420.1244.

[0139] Experimental Example 1: Inhibitory Activity of γ-CF3 Pyridine Compounds on Colon Cancer Cells

[0140] 1. Experimental methods:

[0141] The γ-CF3 pyridine compounds obtained in Examples 1 to 15 were prepared into a certain concentration gradient (0.015 mM to 100 mM) and (0.015 μM to 100 μM), respectively, (M is the molar concentration unit, mol / L). The effects of the compounds on the viability of colon cancer cells (HCT-116) were determined using the MTT colorimetric assay. The cytotoxicity of these compounds was studied using the Cell Counting Kit-8 (CCK-8) assay.

[0142] The specific steps are as follows: Tumor cells were seeded into 96-well plates (3000 cells / well) and cultured overnight. The cells were then incubated with the compounds at concentrations of 0, 0.015, 0.046, 0.14, 0.41, 1.23, 3.7, 11.11, 33.33, and 100 mM / μM for 72 hours. Subsequently, 20 μL of CCK-8 solution (Beyotime, Shanghai Biyuntian Biotechnology Co., Ltd.) was added to each well and incubated for 4 hours. The absorbance of each sample was measured at 450 nm using a microplate reader (Tecan Infinite M1000 Pro). The relative cell viability of each sample was normalized to a DMSO control. The IC50 value is used to measure the level of inhibition or activity of a compound or drug on a biological system. The IC50 value of the γ-CF3 pyridine compound against tumor cells was calculated using cell viability. (Cell viability % = OD570 of the treated group / average OD570 of the blank control group × 100%).

[0143] 2. Experimental results:

[0144] The experimental results are shown in Table 1.

[0145] Table 1 IC50 values of γ-CF3 pyridine compounds against colon cancer cells (HCT-116)

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[0152] As shown in Table 1, the γ-CF3 pyridine compounds prepared in Examples 1 to 15 of the present invention have inhibitory activity against colon cancer cells (HCT-116), providing a new direction for the research and development of new drugs for colon cancer.

Claims

1. A γ-trifluoromethylpyridine compound, characterized in that The γ-trifluoromethylpyridine compound is shown in Formula III: Among them, R 1 is any of alkyl and aryl groups, R 2 、R 3 is an alkyl group, R 4 It is any one of methyl, aryl, and H.

2. A method for synthesizing γ-trifluoromethylpyridine compounds, characterized in that: The following steps are involved: Allyl carboxylate, N-aminopyridinium salt, sodium trifluoromethanesulfinate, sodium acetate and tris(2,2'-bipyrazine)ruthenium di(hexafluoroborate) salt are mixed, and an organic solvent is added under an inert gas environment. Under green light irradiation, magnetic stirring is carried out until the reaction is completed, and the mixture is concentrated under reduced pressure, separated and purified to obtain a compound of formula III.

3. The method for synthesizing γ-trifluoromethylpyridine compounds according to claim 2, wherein: The allyl carboxylate is shown in Formula I: Among them, R 1 is any one of C1-C3 alkyl and aryl, R 2 、R 3 It is a C1-C3 alkyl group.

4. The method for synthesizing γ-trifluoromethylpyridine compounds according to claim 2, wherein: The N-aminopyridinium salt is shown in Formula II: Among them, R 4 It is any one of methyl, aryl, and H.

5. The method for synthesizing γ-trifluoromethylpyridine compounds according to claim 2, wherein: The molar ratio of the allyl carboxylate, N-aminopyridinium salt and sodium trifluoromethanesulfinate is 0.1mmoL:0.2mmoL:0.15mmoL.

6. The method for synthesizing γ-trifluoromethylpyridine compounds according to claim 2, wherein: The molar ratio of the sodium acetate to the allyl carboxylate is 0.15 mmoL:0.1 mmoL.

7. The method for synthesizing γ-trifluoromethylpyridine compounds according to claim 2, wherein: The molar ratio of tris(2,2'-bipyrazine)ruthenium di(hexafluoroborate) salt to allyl carboxylate is 0.002 mmol:0.1 mmol.

8. The method for synthesizing γ-trifluoromethylpyridine compounds according to claim 2, wherein: The organic solvent is one of acetonitrile and 1,2-dichloroethane.

9. The method for synthesizing γ-trifluoromethylpyridine compounds according to claim 2, wherein: The green light irradiation conditions are: wavelength 525 nm, light intensity 40 watts, and irradiation time 12 to 20 hours.

10. Use of the γ-trifluoromethylpyridine compound according to claim 1 in the preparation of a drug for preventing or treating colorectal cancer.

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