A beta'-thio-alpha, beta-unsaturated gamma-lactam derivative, its preparation method and application

Abstract

The application provides a beta'-thio-alpha, beta-unsaturated gamma-lactam derivative and a preparation method and application thereof, and belongs to the technical field of organic chemical synthesis. The beta'-thio-alpha, beta-unsaturated gamma-lactam derivative has a structure shown in formula I. The method constructs a beta'-thio-alpha, beta-unsaturated gamma-lactam derivative molecular skeleton through a free radical coupling and olefin isomerization process under the condition of blue light irradiation with cesium carbonate as an alkali. Through biological activity evaluation, it is found that the beta'-thio-alpha, beta-unsaturated gamma-lactam derivative prepared by the method has an inhibitory effect on MDA-MB-231 human breast cancer cells.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, and in particular to a β'-thio-α,β-unsaturated γ-lactam derivative, its preparation method, and its application. Background Technology

[0002] Thiose ethers are a class of organic compounds containing thioether bonds (CSCs), playing a crucial role in various fields such as organic synthesis, materials science, and medicinal chemistry. In medicinal chemistry, the thioether structure is a key component of many drug molecules; the lone pair of electrons from the sulfur atom endows thioethers with unique biological activity and pharmacokinetic properties. Taking cephalosporins as an example, the thioether bond is central to their molecular structure and plays a decisive role in their antibacterial activity. Furthermore, many drugs for treating cardiovascular and nervous system diseases also contain thioether structures, which can significantly affect the binding affinity between the drug and its target, thereby modulating the drug's efficacy.

[0003] In organic synthesis, thioethers are indispensable intermediates. Through reactions such as oxidation, reduction, and nucleophilic substitution, thioethers can be converted into other sulfur-containing compounds such as sulfoxides, sulfones, and thiols. At the biochemical level, thioethers also play important roles in living organisms. Methionine, one of the basic amino acids that make up proteins, contains thioether bonds in its molecule. Furthermore, some coenzymes and enzymes also have thioether structures in their active sites, deeply involved in various chemical reactions within organisms, maintaining the normal functioning of life activities.

[0004] With the expanding applications of thioethers, their synthetic methods have attracted considerable attention. Currently, common synthetic methods include nucleophilic substitution reactions of halogenated hydrocarbons with thiols (or thiophenols), addition reactions of thiols with alkenes (J.Med.Chem.2020,63,14951–14978), and reactions of organometallic compounds with thiols. However, these methods all have certain limitations. In the Williamson synthesis, tertiary halogenated hydrocarbons readily undergo elimination reactions to form alkenes; sterically hindered reactants have slow reaction rates, and the odor of thiols can harm health and the environment. The Michael addition reaction is catalyst-dependent, and its selection and amount significantly affect the reaction yield and selectivity. The reaction of sulfides with halogenated hydrocarbons requires anhydrous conditions, is prone to hydrolysis producing harmful gases, and generates byproducts that affect purity. The reaction of organometallic compounds with thiols is not only demanding and costly, but also exhibits poor selectivity for compounds containing active hydrogen.

[0005] Given the shortcomings of existing synthetic methods, researchers are actively exploring new synthetic methods and reaction conditions in order to improve the yield, selectivity, and atom economy of thioether synthesis, so as to meet the growing application demands and promote the further development of related fields. Summary of the Invention

[0006] In view of this, the present invention aims to provide a β'-thio-α,β-unsaturated γ-lactam derivative, its preparation method, and its applications. The method of the present invention uses cesium carbonate as a base and constructs the molecular skeleton of the β'-thio-α,β-unsaturated γ-lactam derivative under blue light irradiation through free radical coupling and olefin isomerization. Bioactivity evaluation revealed that the β'-thio-α,β-unsaturated γ-lactam derivative prepared by the method of the present invention has an inhibitory effect on MDA-MB-231 human breast cancer cells.

[0007] To achieve the above objectives, the present invention provides the following technical solution:

[0008] One of the technical solutions of this invention is a β'-thio-α,β-unsaturated γ-lactam derivative having the structure shown in Formula I:

[0009]

[0010] Among them, R 1 It is phenyl, 4-methylphenyl, 3-methylphenyl, 4-methoxyphenyl, 3,4-dichlorophenyl, 1-naphthyl, 4-Cl-3-pyridyl, 4,4-difluorocyclohexyl, 2-naphthylmethyl or 4-fluorobenzoyl; R 2 It is 4-methylphenyl, 4-methoxyphenyl, 3,5-difluorophenyl, 4-(N-acetyl)phenyl, 2-naphthyl or methyl 2-carboxylate phenyl.

[0011] The second technical solution of the present invention is a method for preparing the above-mentioned β'-thio-α,β-unsaturated γ-lactam derivative, which uses β-chloro-β-polyfluoroalkylmethylene γ-lactam compound and thiophenol derivative as raw materials, cesium carbonate as base, and reacts under blue light irradiation to obtain the β'-thio-α,β-unsaturated γ-lactam derivative.

[0012] The β-chloro-β-polyfluoroalkylmethylene γ-lactam compound has the structure shown in Formula II:

[0013] The thiophenol derivative has the structure shown in Formula III: R 2 -SH;

[0014] In Equation II, R 1 In formula I, R 1 Similarly, R in Equation III 2 In formula I, R 2 same.

[0015] The third technical solution of the present invention is the application of the above-mentioned β'-thio-α,β-unsaturated γ-lactam derivative in the preparation of a drug for treating MDA-MB-231 human breast cancer.

[0016] The fourth technical solution of the present invention is a drug for treating MDA-MB-231 human breast cancer cells, the raw materials of which include the above-mentioned β'-thio-α,β-unsaturated γ-lactam derivatives and pharmaceutically acceptable excipients.

[0017] The present invention discloses the following technical effects:

[0018] The β'-thio-α,β-unsaturated γ-lactam derivative provided by this invention has a significant inhibitory effect on MDA-MB-231 human breast cancer cells.

[0019] The preparation method provided by this invention has mild reaction conditions, high reaction efficiency, low cost, and simple operation, and has good prospects for industrial application. Detailed Implementation

[0020] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0021] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0022] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0023] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0024] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0025] Unless otherwise specified, room temperature in this invention refers to 25±5℃.

[0026] The first aspect of this invention provides a β'-thio-α,β-unsaturated γ-lactam derivative having the structure shown in Formula I:

[0027]

[0028] Among them, R 1 It is phenyl, 4-methylphenyl, 3-methylphenyl, 4-methoxyphenyl, 3,4-dichlorophenyl, 1-naphthyl, 4-Cl-3-pyridyl, 4,4-difluorocyclohexyl, 2-naphthylmethyl or 4-fluorobenzoyl; R 2 It is 4-methylphenyl, 4-methoxyphenyl, 3,5-difluorophenyl, 4-(N-acetyl)phenyl, 2-naphthyl or methyl 2-carboxylate phenyl.

[0029] In a preferred embodiment of the present invention, the β'-thio-α,β-unsaturated γ-lactam derivative is selected from one of the following structural formulas:

[0030]

[0031] The second aspect of the present invention provides a method for preparing the above-mentioned β'-thio-α,β-unsaturated γ-lactam derivative, using β-chloro-β-polyfluoroalkylmethylene γ-lactam compound and thiophenol derivative as raw materials, cesium carbonate as base, and reacting under blue light irradiation to obtain the β'-thio-α,β-unsaturated γ-lactam derivative.

[0032] The β-chloro-β-polyfluoroalkylmethylene γ-lactam compound has the structure shown in Formula II:

[0033] The thiophenol derivative has the structure shown in Formula III: R 2 -SH;

[0034] In Equation II, R 1 In formula I, R 1 Similarly, R in Equation III 2 In formula I, R 2 same.

[0035] The general reaction formula is:

[0036]

[0037] In a preferred embodiment of the present invention, the molar ratio of the β-chloro-β-polyfluoroalkylmethylene γ-lactam compound and the thiophenol derivative is 1:(1.2 to 1.5).

[0038] In a preferred embodiment of the present invention, the molar ratio of the β-chloro-β-polyfluoroalkylmethylene γ-lactam compound to the cesium carbonate is 1:(1.2 to 1.5).

[0039] In a preferred embodiment of the present invention, the power of the blue light is 3W to 10W, and the reaction time is 10min to 6h.

[0040] In a preferred embodiment of the present invention, the temperature during the reaction is room temperature.

[0041] In this invention, the above reaction system is carried out in an organic solvent, preferably acetonitrile. This invention does not impose a specific limit on the amount of acetonitrile used, as long as it is sufficient to allow the reaction to proceed. For example, the ratio of the β-chloro-β-trifluoromethyl-α-methylene-γ-lactam compound to the organic solvent is 0.3 mmol: 1–3 mL.

[0042] In a preferred embodiment of the present invention, after the reaction is completed, the method further includes the steps of separating and purifying the obtained product.

[0043] In a preferred embodiment of the present invention, the separation is performed by liquid phase extraction; the purification is performed by column chromatography.

[0044] In a preferred embodiment of the present invention, the separation and purification specifically involves: extraction with ethyl acetate, collection of the ethyl acetate layer after extraction, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, vacuum concentration to remove the ethyl acetate, and then separation by silica gel column chromatography with gradient elution.

[0045] A third aspect of the present invention provides the use of the above-mentioned β'-thio-α,β-unsaturated γ-lactam derivative in the preparation of a drug for treating human breast cancer MDA-MB-231.

[0046] The fourth aspect of the present invention provides a medicament for treating MDA-MB-231 human breast cancer cells, comprising the above-mentioned β'-thio-α,β-unsaturated γ-lactam derivatives and pharmaceutically acceptable excipients.

[0047] Unless otherwise specified, the technical solutions described in this invention are all conventional solutions in the field, and the reagents or raw materials used are all purchased from commercial channels or are publicly available unless otherwise specified.

[0048] In this embodiment of the invention, the antitumor activity of β'-thio-α,β-unsaturated γ-lactam derivatives against tumor cells was evaluated by an in vitro cell proliferation and toxicity assay (CCK-8 assay), and compounds with good activity against tumor cells were screened out.

[0049] Cells were observed under a microscope. When the cells adhered and grew to 80%-90%, the culture dishes were sterilized and placed in a clean bench. The cells were washed twice with prepared PBS buffer and the central area was agitated with fresh culture medium. The cell suspension was then transferred to centrifuge tubes. Next, 10 μL of the cell suspension was pipetted into a cell counting chamber, and cell counting was performed using a cell counter. Cells were cultured in 96-well plates at a seeding density of 5000 cells per well (50000 cells / mL, 100 μL of cell suspension added). The plates were incubated in a CO2 cell culture incubator for 24 h until the cells adhered. The compounds to be tested were diluted with culture medium to the corresponding concentrations (5 μmol / L, 10 μmol / L, 20 μmol / L, 40 μmol / L, 60 μmol / L, 80 μmol / L) and added to 96-well plates already seeded with MDA-MB-231 cells, 100 μL per well, with 6 replicates. The plates were then incubated in a cell culture incubator. After 24 hours, remove the samples, add 100 μL of CCK-8 reagent to each well, incubate for 2 hours, and then detect the results using a microplate reader. Calculate the IC50 using GraphPad. 50 .

[0050] To better understand the present invention, the following embodiments further illustrate the content of the present invention, but the content of the present invention is not limited to the following embodiments.

[0051] Example 1

[0052] Weighed 3-(1-chloro-2,2,2-trifluoroethyl)-1-phenylpyrrolidone-2-one (0.2 mmol), p-methoxythiophenol (0.24 mmol), cesium carbonate (0.3 mmol), and acetonitrile (2 mL) were added sequentially to a 25 mL Shrek tube. The mixture was irradiated with 3 W blue light under a nitrogen atmosphere and stirred at room temperature for 1 h. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate (15 mL × 3), the ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate (30 / 1-10 / 1)) to give a yellow solid in 89% yield.

[0053] The reaction equation is as follows:

[0054]

[0055] The structural characterization data of the obtained target product are shown below:

[0056] 1 H NMR(400MHz,Chloroform-d)δ7.75(d,J=7.8Hz,2H),7.52(d,J=8.1Hz,2H),7.40(d,J=8.5Hz,2 H),7.16(t,J=7.6Hz,3H),6.93(s,1H),4.60(q,J=8.7Hz,1H),4.41–4.27(m,2H),2.35(s,3H);

[0057] 13 C NMR(100MHz,Chloroform-d)δ167.6,139.7,138.9,138.2,135.3,133.0,129.9,1 29.3,128.5,125.7(q,J=279.3Hz),124.7,118.9,51.6,46.8(q,J=31.1Hz),21.3;

[0058] 19 F NMR(376MHz,Chloroform-d)δ-67.99;

[0059] HRMS(ESI)m / z calcd for C 19 H 17 F3NOS + [M+H] + 364.0977, found 364.0978.

[0060] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0061]

[0062] This compound has an inhibitory effect on MDA-MB-231 human breast cancer cells, IC50. 50 It is 36.27±0.42μM.

[0063] Example 2

[0064] To a 25 mL Shrek tube, add weighed 3-(1-chloro-2,2,2-trifluoroethyl)-1-p-methylphenylpyrrolidone-2-one (0.2 mmol), p-methoxythiophenol (0.24 mmol), cesium carbonate (0.3 mmol), and acetonitrile (2 mL). Replace with nitrogen gas, then purge with nitrogen and stir at room temperature for 1 h under 3 W blue light irradiation. After the reaction is complete, quench the reaction with a saturated ammonium chloride solution, extract with ethyl acetate (15 mL × 3), wash the ethyl acetate layer with a saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under vacuum, and separate by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate (30 / 1-10 / 1)) to obtain a yellow solid in 78% yield.

[0065] The reaction equation is as follows:

[0066] The structural characterization data of the obtained target product are shown below:

[0067] 1 H NMR(400MHz,Chloroform-d)δ7.51(d,J=7.9Hz,2H),7.44(d,J=8.1Hz,2H),7.11(d,J=7.8Hz,2 H),6.76(d,J=8.7Hz,3H),4.42(q,J=8.3Hz,1H),4.32–4.12(m,2H),3.71(s,3H),2.25(s,3H);

[0068] 13 C NMR(100MHz,Chloroform-d)δ167.4,160.9137.9,137.8,136.4,134.4,132.8,129.8 ,125.9(q,J=278.7Hz),122.4,119.0,114.6,55.4,51.7,47.11(q,J=30.9Hz),20.9;

[0069] 19 F NMR(376MHz,Chloroform-d)δ-67.82;

[0070] HRMS(ESI)m / z calcd for C 20 H 19 F3NO2S + [M+H] + 394.1083, found 394.1087.

[0071] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0072]

[0073] This compound has an inhibitory effect on MDA-MB-231 human breast cancer cells, IC50. 50 The value was 40.25 ± 0.61 μM.

[0074] Example 3

[0075] To a 25 mL Shrek tube, add weighed 3-(1-chloro-2,2,2-trifluoroethyl)-1-m-methylphenylpyrrolidone-2-one (0.2 mmol), p-methoxythiophenol (0.24 mmol), cesium carbonate (0.3 mmol), and acetonitrile (2 mL). Replace with nitrogen gas, then purge with nitrogen and stir at room temperature for 1 h under 3 W blue light irradiation. After the reaction is complete, quench the reaction with a saturated ammonium chloride solution, extract with ethyl acetate (15 mL × 3), wash the ethyl acetate layer with a saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under vacuum, and separate by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate (30 / 1-10 / 1)) to obtain a yellow solid in 81% yield.

[0076] The reaction equation is as follows:

[0077]

[0078] The structural characterization data of the obtained target product are shown below:

[0079] 1 HNMR(400MHz,Chloroform-d)δ7.59(s,1H),7.53–7.45(m,3H),7.28(s,1H),6.97(d,J=7.5Hz ,1H),6.85–6.81(m,3H),4.49(q,J=8.8Hz,1H),4.40–4.22(m,2H),3.78(s,3H),2.37(s,3H);

[0080] 13 C NMR(100MHz,Chloroform-d)δ167.6,160.9,139.3,138.9,138.0,137.8,129.1,126.6(q, J=278.6Hz),125.63,122.43,119.8,116.1,114.7,55.5,51.8,47.1(q,J=30.8Hz),21.8;

[0081] 19 F NMR(376MHz,Chloroform-d)δ-67.81

[0082] HRMS(ESI)m / z calcd for C 20 H 19 F3NO2S + [M+H] + 394.1083, found 394.1086.

[0083] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0084]

[0085] This compound has an inhibitory effect on MDA-MB-231 human breast cancer cells, IC50. 50 The value was 42.38 ± 0.64 μM.

[0086] Example 4

[0087] Weighed 3-(1-chloro-2,2,2-trifluoroethyl)-1-p-methoxyphenylpyrrolidone-2-one (0.2 mmol), p-methoxythiophenol (0.24 mmol), cesium carbonate (0.3 mmol), and acetonitrile (2 mL) were added sequentially to a 25 mL Shrek tube. Nitrogen gas was then introduced, and the mixture was stirred at room temperature for 1 h under 3 W blue light irradiation. After the reaction was complete, the reaction was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate (15 mL × 3), washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate (30 / 1-10 / 1)) to give a brown solid in 75% yield.

[0088] The reaction equation is as follows:

[0089]

[0090] The structural characterization data of the obtained target product are shown below:

[0091] 1 H NMR(400MHz,Chloroform-d)δ7.63–7.58(m,2H),7.56–7.50(m,2H),6.94–6.90(m,2H),6. 83(dd,J=7.7,5.7Hz,3H),4.51(q,J=8.8Hz,1H),4.36–4.21(m,2H),3.79(d,J=5.0Hz,6H).

[0092] 13C NMR(100MHz,Chloroform-d)δ167.3,160.9,156.8,137.8,135.3,132.7,132.1,125.9(q,J= 278.7Hz), 122.5, 121.5, 120.9, 114.6, 114.5, 55.5 (d, J = 14.9Hz), 52.1, 47.1 (q, J = 30.9Hz).

[0093] 19 F NMR(376MHz,Chloroform-d)δ-67.84.

[0094] HRMS(ESI)m / z calcd for C 20 H 19 F3NO3S + [M+H] + 410.1032, found 410.1034.

[0095] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0096]

[0097] This compound had no inhibitory effect on MDA-MB-231 human breast cancer cells, IC50. 50 Greater than 80μM.

[0098] Example 5

[0099] To a 25 mL Shrek tube, add weighed 3-(1-chloro-2,2,2-trifluoroethylene)-1-(3,4-dichlorophenyl)pyrrolidone-2-one (0.2 mmol), p-methoxythiophenol (0.24 mmol), cesium carbonate (0.3 mmol), and acetonitrile (2 mL). Replace with nitrogen gas, then purge with nitrogen and stir at room temperature for 1 h under 3 W blue light irradiation. After the reaction is complete, quench the reaction with a saturated ammonium chloride solution, extract with ethyl acetate (15 mL × 3), wash the ethyl acetate layer with a saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under vacuum, and separate by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate (30 / 1-10 / 1)) to give a brown solid in 70% yield.

[0100] The reaction equation is as follows:

[0101]

[0102] The structural characterization data of the obtained target product are shown below:

[0103] 1H NMR(400MHz,Chloroform-d)δ7.94(d,J=2.6Hz,1H),7.63(dd,J=8.9,2.6Hz,1H),7.52(d,J=8.7Hz,2H),7.44(d,J =8.9Hz,1H),6.87(t,J=3.3Hz,2H),6.85(d,J=2.1Hz,1H),4.46(q,J=8.7Hz,1H),4.40–4.24(m,2H),3.81(s,3H);

[0104] 13 C NMR(100MHz,Chloroform-d)δ161.1,138.4,138.2,137.8,133.3,132.9,130.9,1 27.9,124.9(q,J=278.5Hz),120.2,117.7,114.8,55.5,51.4,47.1(q,J=30.9Hz);

[0105] 19 F NMR(376MHz,Chloroform-d)δ-67.81;

[0106] HRMS(ESI)m / z calcd for C 19 H 15 Cl2F3NO2S + [M+H] + 488.0147, found 488.0151.

[0107] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0108]

[0109] This compound has an inhibitory effect on MDA-MB-231 human breast cancer cells, IC50. 50 The value was 43.03 ± 0.68 μM.

[0110] Example 6

[0111] To a 25 mL Shrek tube, add weighed 3-(1-chloro-2,2,2-trifluoroethyl)-1-(1-naphthyl)-pyrrolidone-2-one (0.2 mmol), p-methoxythiophenol (0.24 mmol), cesium carbonate (0.3 mmol), and acetonitrile (2 mL). Replace with nitrogen gas, then purge with nitrogen and stir at room temperature for 1 h under 3 W blue light irradiation. After the reaction is complete, quench the reaction with a saturated ammonium chloride solution, extract with ethyl acetate (15 mL × 3), wash the ethyl acetate layer with a saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under vacuum, and separate by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate (30 / 1-10 / 1)) to obtain a yellow liquid with a yield of 67%.

[0112] The reaction equation is as follows:

[0113]

[0114] The structural characterization data of the obtained target product are shown below:

[0115] 1 H NMR(400MHz,Chloroform-d)δ7.82–7.74(m,2H),7.52–7.38(m,6H),7.28(d,J=6.5Hz,1H), 6.92(s,1H),6.74(t,J=9.1Hz,2H),4.50(q,J=8.2Hz,1H),4.36–4.14(m,2H),3.67(s,3H);

[0116] 13 C NMR(100MHz,Chloroform-d)δ168.8,160.9,139.6,137.8,134.7,134.4,131.9,130.5,128.9,128.7,1 27.1,126.6,126.0(q,J=278.7Hz),125.6,125.6,122.8,122.7,114.6,55.4,55.1,47.5(q,J=30.8Hz);

[0117] 19 F NMR(376MHz,Chloroform-d)δ-67.83;

[0118] HRMS(ESI)m / z calcd forC 23 H 19 F3NO2S + [M+H] + 430.1083, found 430.1086.

[0119] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0120]

[0121] This compound has an inhibitory effect on MDA-MB-231 human breast cancer cells, IC50. 50 The value was 19.64 ± 0.72 μM.

[0122] Example 7

[0123] To a 25 mL Shrek tube, weighed 3-(1-chloro-2,2,2-trifluoroethylene)-1-(6-chloropyridine)pyrrolidine-2-one (0.2 mmol), p-methoxythiophenol (0.24 mmol), cesium carbonate (0.3 mmol), and acetonitrile (2 mL) were added sequentially. Nitrogen gas was then introduced, and the mixture was stirred at room temperature for 1 h under 3 W blue light irradiation. After the reaction was complete, the reaction was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate (15 mL × 3), washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate (30 / 1-10 / 1)) to give a yellow solid in 71% yield.

[0124] The reaction equation is as follows:

[0125]

[0126] The structural characterization data of the obtained target product are shown below:

[0127] 1H NMR(400MHz,Chloroform-d)δ8.54(d,J=2.8Hz,1H),8.40(dd,J=8.8Hz,1H),7.54–7.47(m,2H),7.35 (d,J=8.8Hz,1H),6.91(s,1H),6.87–6.82(m,2H),4.51–4.43(m,1H),4.43–4.30(m,2H),3.80(s,3H);

[0128] 13C NMR(100MHz,Chloroform-d)δ167.9,161.1,146.3,138.8,138.7,137.8,134.8,132. 6,128.8,125.7(q,J=278.8Hz),124.6,122.0,114.7,55.5,50.8,46.9(q,J=31.0Hz);

[0129] 19F NMR (376MHz, Chloroform-d) δ-67.81;

[0130] HRMS(ESI)m / z calcd for C 18 H 15 ClF3N2O2S + [M+H] + 415.0489, found 415.0493.

[0131] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0132]

[0133] This compound had no inhibitory effect on MDA-MB-231 human breast cancer cells, IC50. 50 Greater than 80μM.

[0134] Example 8

[0135] To a 25 mL Shrek tube, weighed 3-(1-chloro-2,2,2-trifluoroethyl)-1-(4,4-difluorocyclohexyl)pyrrolidone-2-one (0.2 mmol), p-methoxythiophenol (0.24 mmol), cesium carbonate (0.3 mmol), and acetonitrile (2 mL) were added sequentially. Nitrogen gas was then introduced, and the mixture was stirred at room temperature for 6 h under 10 W blue light irradiation. After the reaction was complete, the reaction was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate (15 mL × 3), washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate (30 / 1-10 / 1)) to give a yellow solid in 67% yield.

[0136] The reaction equation is as follows:

[0137]

[0138] The structural characterization data of the obtained target product are shown below:

[0139] 1H NMR(400MHz,Chloroform-d)δ7.48(d,J=8.8Hz,2H),6.83(d,J=8.9Hz,2H),6.76(s,1H),4.11(q,J= 7.1Hz,1H),3.79(s,5H),2.27–2.12(m,3H),2.03(s,1H),1.93–1.84(m,3H),1.75(d,J=13.3Hz,2H);

[0140] 13C NMR(100MHz,Chloroform-d)δ168.6,160.9,138.5,137.8,131.9,125.8(q,J=278.7Hz),122.5,1 14.6, 55.5, 49.0, 47.6, 47.2 (q, J = 30.9Hz), 32.9 (ddd, J = 26.2, 24.3, 2.5Hz), 27.2 (t, J = 9.8Hz);

[0141] 19F NMR (376MHz, Chloroform-d) δ -67.97, -93.79 (d, J = 238.7Hz), -102.76 (d, J = 238.6Hz);

[0142] HRMS(ESI)m / z calcd for C 19 H 21 F5NO2S + [M+H] + 422.1208, found 422.1207.

[0143] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0144]

[0145] This compound had no inhibitory effect on MDA-MB-231 human breast cancer cells, IC50. 50 Greater than 80μM.

[0146] Example 9

[0147] To a 25 mL Shrek tube, weighed 3-(1-chloro-2,2,2-trifluoroethyl)-1-(2-naphthylmethyl)pyrrolidone-2-one (0.2 mmol), p-methoxythiophenol (0.24 mmol), cesium carbonate (0.3 mmol), and acetonitrile (2 mL) were added sequentially. Nitrogen gas was then introduced, and the mixture was stirred at room temperature for 6 h under 10 W blue light irradiation. After the reaction was complete, the reaction was quenched with a saturated ammonium chloride solution, extracted with ethyl acetate (15 mL × 3), washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under vacuum, and separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate (30 / 1-10 / 1)) to obtain a yellow liquid with a yield of 73%.

[0148] The reaction equation is as follows:

[0149]

[0150] The structural characterization data of the obtained target product are shown below:

[0151] 1 H NMR(400MHz,Chloroform-d)δ8.20(d,J=8.4Hz,1H),7.87(dd,J=15.9,8.0Hz,2H),7.63–7.38(m,6H),6.58(d,J=8.6Hz,2H),6.5 3(s,1H),5.27(d,J=14.6Hz,1H),4.96(d,J=14.7Hz,1H),4.53(q,J=8.8Hz,1H),3.65(d,J=20.9Hz,4H),3.45(d,J=20.4Hz,1H);

[0152] 13 C NMR(100MHz,Chloroform-d)δ172.2–165.8(m),160.8,139.3–138.6(m),138.1,134.1,132.4,131.3,129.2,128. 8,127.6,127.1,126.4,125.9(q,J=278.6Hz),125.4,123.9,121.9,114.3,55.3,50.8,46.9(q,J=30.8Hz),44.9;

[0153] 19 F NMR(376MHz,Chloroform-d)δ-67.81;

[0154] HRMS(ESI)m / z calcd for C 24 H 21 F3NO2S + [M+H] + 444.1240, found 444.1243.

[0155] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0156]

[0157] This compound has an inhibitory effect on MDA-MB-231 human breast cancer cells, IC50. 50 It is 16.41±0.25μM.

[0158] Example 10

[0159] To a 25 mL Shrek tube, add weighed 3-(1-chloro-2,2,2-trifluoroethyl)-1-(4-fluorobenzoyl)pyrrolidone-2-one (0.2 mmol), p-methoxythiophenol (0.24 mmol), cesium carbonate (0.3 mmol), and acetonitrile (2 mL). Replace with nitrogen gas, then purge with nitrogen and stir at room temperature for 15 min under 3 W blue light irradiation. After the reaction is complete, quench the reaction with a saturated ammonium chloride solution, extract with ethyl acetate (15 mL × 3), wash the ethyl acetate layer with a saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under vacuum, and separate by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate (30 / 1-10 / 1)) to obtain a yellow solid in 71% yield.

[0160] The reaction equation is as follows:

[0161]

[0162] The structural characterization data of the obtained target product are shown below:

[0163] 1 H NMR(400MHz,Chloroform-d)δ7.76–7.66(m,2H),7.48–7.43(m,2H),7.18–7.10(m,2H), 7.05(s,1H),6.87–6.83(m,2H),4.63–4.46(m,2H),4.33(q,J=8.6Hz,1H),3.81(s,3H);

[0164] 13 C NMR(100MHz,Chloroform-d)δ168.1,167.2,161.1,142.9,137.8,132.1,131.9,129. 6,125.6(q,J=278.9Hz),121.7,115.4,115.1,114.8,55.5,49.9,46.7(q,J=31.0Hz);

[0165] 19 F NMR(376MHz,Chloroform-d)δ-75.90,-105.39;

[0166] HRMS(ESI)m / z calcd for C 20 H 16 F4NO3S + [M+H] + 426.0782, found 426.0783.

[0167] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0168]

[0169] This compound has an inhibitory effect on MDA-MB-231 human breast cancer cells, IC50. 50 It is 21.65±0.88μM.

[0170] Example 11

[0171] To a 25 mL Shrek tube, add weighed 3-(1-chloro-2,2,2-trifluoroethyl)-1-phenylpyrrolidone-2-one (0.2 mmol), p-methylthiophenol (0.24 mmol), cesium carbonate (0.3 mmol), and acetonitrile (2 mL). Replace with nitrogen gas, then purge with nitrogen and stir at room temperature for 1 h under 3 W blue light irradiation. After the reaction is complete, quench the reaction with a saturated ammonium chloride solution, extract with ethyl acetate (15 mL × 3), wash the ethyl acetate layer with a saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under vacuum, and separate by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate (30 / 1-10 / 1)) to obtain a yellow liquid with a yield of 89%.

[0172] The reaction equation is as follows:

[0173]

[0174] The structural characterization data of the obtained target product are shown below:

[0175] 1 H NMR(400MHz,Chloroform-d)δ7.75(d,J=7.8Hz,2H),7.52(d,J=8.1Hz,2H),7.40(d,J=8.5Hz,2 H),7.16(t,J=7.6Hz,3H),6.93(s,1H),4.60(q,J=8.7Hz,1H),4.41–4.27(m,2H),2.35(s,3H);

[0176] 13 C NMR(100MHz,Chloroform-d)δ167.6,139.7,138.9,138.2,135.3,133.0,129.9,1 29.3,128.5,125.7(q,J=279.3Hz),124.7,118.9,51.6,46.8(q,J=31.1Hz),21.3;

[0177] 19F NMR(376MHz,Chloroform-d)δ-67.99; HRMS(ESI)m / z calcd for C 19 H 17 F3NOS + [M+H] + 364.0977, found 364.0978.

[0178] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0179]

[0180] This compound had no inhibitory effect on MDA-MB-231 human breast cancer cells, IC50. 50 Greater than 80μM.

[0181] Example 12

[0182] To a 25 mL Shrek tube, add weighed 3-(1-chloro-2,2,2-trifluoroethyl)-1-phenylpyrrolidone-2-one (0.2 mmol), 3,5-difluorothiophenol (0.24 mmol), cesium carbonate (0.3 mmol), and acetonitrile (2 mL). Replace with nitrogen gas, then purge with nitrogen and stir at room temperature for 1 h under 3 W blue light irradiation. After the reaction is complete, quench the reaction with a saturated ammonium chloride solution, extract with ethyl acetate (15 mL × 3), wash the ethyl acetate layer with a saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under vacuum, and separate by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate (30 / 1-10 / 1)) to obtain a yellow liquid with a yield of 77%.

[0183] The reaction equation is as follows:

[0184]

[0185] The structural characterization data of the obtained target product are shown below:

[0186] 1 H NMR(400MHz,Chloroform-d)δ7.73(d,J=7.9Hz,2H),7.42(t,J=8.0Hz,2H),7.25–7.16 (m,3H),7.13(s,1H),6.80(tt,J=8.8,2.2Hz,1H),4.69(q,J=8.3Hz,1H),4.46(s,2H);

[0187] 13C NMR(100MHz,Chloroform-d)δ168.3–166.8(m),164.7–163.4(m),161.6(d,J=12.9Hz),138.7,138.5,136.5–135.8 (m),129.4,126.9(q,J=278.7Hz),125.0,119.1,117.5–114.8(m),104.9(t,J=25.2Hz),51.8,46.9(q,J=31.2Hz);

[0188] 19 F NMR(376MHz,Chloroform-d)δ-68.34,-108.11;

[0189] HRMS(ESI)m / z calcd for C 18 H 13 F5NOS + [M+H] + 386.0633, found 386.0635.

[0190] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0191]

[0192] This compound had no inhibitory effect on MDA-MB-231 human breast cancer cells, IC50. 50 Greater than 80μM.

[0193] Example 13

[0194] To a 25 mL Shrek tube, add weighed 3-(1-chloro-2,2,2-trifluoroethyl)-1-phenylpyrrolidone-2-one (0.2 mmol), 4-acetaminothiophenol (0.24 mmol), cesium carbonate (0.3 mmol), and acetonitrile (2 mL). Replace with nitrogen gas, then purge with nitrogen and stir at room temperature for 1 h under 3 W blue light irradiation. After the reaction is complete, quench the reaction with a saturated ammonium chloride solution, extract with ethyl acetate (15 mL × 3), wash the ethyl acetate layer with a saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under vacuum, and separate by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate (30 / 1-10 / 1), yielding a brown liquid with a yield of 67%).

[0195] The reaction equation is as follows:

[0196]

[0197] The structural characterization data of the obtained target product are shown below:

[0198] 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),7.79(d,J=7.8Hz,2H),7.62(dd,J=8.7,1.3Hz,2H),7.49–7.3 8(m,4H),7.19(s,1H),7.16(d,J=7.4Hz,1H),4.76(q,J=8.9Hz,1H),4.68–4.47(m,2H),2.06(s,3H);

[0199] 13 C NMR (100MHz, DMSO-d6) δ169.1,167.4,141.9,140.9,139.3,135.8,130.8,125. 3(q,J=278.9Hz),124.8,124.7,119.9,119.2,52.1,46.4(q,J=30.0Hz),24.5;

[0200] 19 F NMR(376MHz,Chloroform-d)δ-68.18;

[0201] HRMS(ESI)m / z calcd for C 20 H 18 F3N2O2S + [M+H] + 407.1036, found 407.1037.

[0202] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0203]

[0204] This compound has an inhibitory effect on MDA-MB-231 human breast cancer cells, IC50. 50 The value was 46.46 ± 0.73 μM.

[0205] Example 14

[0206] To a 25 mL Shrek tube, add weighed 3-(1-chloro-2,2,2-trifluoroethyl)-1-phenylpyrrolidone-2-one (0.2 mmol), 2-naphthiol (0.24 mmol), cesium carbonate (0.3 mmol), and acetonitrile (2 mL). Replace with nitrogen gas, then purge with nitrogen and stir at room temperature for 1 h under 3 W blue light irradiation. After the reaction is complete, quench the reaction with a saturated ammonium chloride solution, extract with ethyl acetate (15 mL × 3), wash the ethyl acetate layer with a saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under vacuum, and separate by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate (30 / 1-10 / 1)) to obtain a yellow liquid with a yield of 71%.

[0207] The reaction equation is as follows:

[0208]

[0209] The structural characterization data of the obtained target product are shown below:

[0210] 1 HNMR(400MHz,Chloroform-d)δ8.14–8.10(m,1H),7.85–7.80(m,3H),7.73(ddd,J=12.0Hz,3H),7.54–7.49 (m,2H),7.42(td,J=7.6Hz,2H),7.22–7.16(m,1H),6.96(s,1H),4.78(q,J=8.6Hz,1H),4.42–4.24(m,2H);

[0211] 13 C NMR(100MHz,Chloroform-d)δ167.6,138.9,138.4,134.6,133.5,133.3,133.0,131.2,129.4 ,129.4,129.0,128.0,127.8,126.3(q,J=278.8Hz),126.8,118.9,51.7,46.6(q,J=31.3Hz);

[0212] 19 F NMR(376MHz,Chloroform-d)δ-67.93;

[0213] HRMS(ESI)m / z calcd for C 22 H 17 NF3NOS + [M+H] + 400.0977, found 400.0981.

[0214] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0215]

[0216] This compound has an inhibitory effect on MDA-MB-231 human breast cancer cells, IC50. 50 The value was 46.24 ± 0.72 μM.

[0217] Example 15

[0218] To a 25 mL Shrek tube, add weighed 3-(1-chloro-2,2,2-trifluoroethyl)-1-phenylpyrrolidone-2-one (0.2 mmol), methyl thiosalicylate (0.24 mmol), cesium carbonate (0.3 mmol), and acetonitrile (2 mL). Replace with nitrogen gas, then purge with nitrogen and stir at room temperature for 1 h under 3 W blue light irradiation. After the reaction is complete, quench the reaction with a saturated ammonium chloride solution, extract with ethyl acetate (15 mL × 3), wash the ethyl acetate layer with a saturated sodium chloride solution, dry to anhydrous sodium sulfate, concentrate under vacuum, and separate by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate (30 / 1-10 / 1)) to obtain a yellow liquid in 80% yield.

[0219] The reaction equation is as follows:

[0220]

[0221] The structural characterization data of the obtained target product are shown below:

[0222] 1 H NMR(400MHz,Chloroform-d)δ7.88(dd,J=7.8,Hz,1H),7.72–7.27(m,7H),7.23 (s,1H),7.14(t,J=7.4Hz,1H),4.99(q,J=8.2Hz,1H),4.40(s,2H),3.89(s,3H);

[0223] 13 C NMR(100MHz,Chloroform-d)δ167.6,167.0,139.8,138.8,136.1,133.6,132.8,131.0,130.0,1 29.32126.9(q,J=278.9Hz),126.8,124.8,118.9,118.6,52.5,51.8,43.8(q,J=31.5Hz),43.3;

[0224] 19 F NMR(376MHz,Chloroform-d)δ-67.91;

[0225] HRMS(ESI)m / z calcd for C 20 H 17 F3NO3S + [M+H] + 408.0876, found 408.0878.

[0226] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0227]

[0228] This compound had no inhibitory effect on MDA-MB-231 human breast cancer cells, IC50. 50 Greater than 80μM.

[0229] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A kind β’ -Thio- α,β -Unsaturated γ - Lactam derivatives, characterized in that It has the following structure: 。 2. The one described in claim 1 β’ -Thio- α,β -Unsaturated γ The method for preparing β-lactam derivatives is characterized by, by β -chloro- β -Polyfluoroalkylmethylene γ Using β'-thio-α,β-unsaturated γ-lactam derivatives as raw materials and cesium carbonate as a base, the reaction is carried out under blue light irradiation to obtain the β'-thio-α,β-unsaturated γ-lactam derivative. The β -chloro- β -Polyfluoroalkylmethylene γ - Lactam compounds have the structure shown in Formula II: Formula II; The thiophenol derivative has the structure shown in Formula III: Formula III; In Equation II, R 1 and the specific structure of claim 1 β’ -Thio- α,β -Unsaturated γ - The groups at the corresponding positions of the lactam derivatives are consistent, and R in Formula III 2 and the specific structure of claim 1 β’ -Thio- α,β -Unsaturated γ - The groups at the corresponding positions of the lactam derivatives are consistent.

3. The preparation method according to claim 2, characterized in that, The β -chloro- β -Polyfluoroalkylmethylene γ The molar ratio of the β-lactam compound to the thiophenol derivative is 1:(1.2~1.5).

4. The preparation method according to claim 2, characterized in that, The β -chloro- β -Polyfluoroalkylmethylene γ The molar ratio of the β-lactam compound to the cesium carbonate is 1:(1.2~1.5).

5. The preparation method according to claim 2, characterized in that, The power of the blue light is 3 W to 10 W, and the reaction time is 10 min to 6 h.

6. The preparation method according to claim 2, characterized in that, After the reaction is completed, the process also includes the steps of separating and purifying the resulting product.

7. The one described in claim 1 β’ -Thio- α,β -Unsaturated γ Application of β-lactam derivatives in the preparation of drugs for treating MDA-MB-231 human breast cancer cells.

8. A drug for treating MDA-MB-231 human breast cancer cells, characterized in that, The raw materials include those described in claim 1. β’ -Thio- α,β -Unsaturated γ - Lactam derivatives and pharmaceutically acceptable excipients.

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