A fluorinated alkylthio ketene and its use in the synthesis of fluorinated alkylthio pyrazoles

Abstract

This invention belongs to the field of organic synthesis chemistry, specifically relating to a fluoroalkylthio-acetal ketone and its application in the synthesis of fluoroalkylthiopyrazoles. The general formula of the fluoroalkylthio-acetal ketone compound is shown as (Ⅰ); wherein, R 1 Selected from acyl groups; R 2 Selected from one of ester, acyl, or amide groups; R f Selected from one of monofluoroalkyl or difluoroalkyl groups. The general formula II for fluoroalkylthiopyrazole compounds is shown: (II)R 1 Selected from either ester or cyano groups; R 2 Selected from alkyl or aryl; R 3 Selected from either aryl or hydrogen atoms; R f Selected from monofluoroalkyl groups. The compound shown in general formula II has certain inhibitory activity against the growth of human endometrial adenocarcinoma cells (HEC-1-B) and human fibrosarcoma cells (HT-1080).

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis chemistry technology, specifically relating to a fluoroalkylthio-encapsulated ketone and its application in the synthesis of fluoroalkylthio-pyrazole. Background Technology

[0002] Since Kelber first synthesized α-benzoyl dithiocarbamate in 1910, α-carbonyl dithiocarbamate chemistry has occupied an important position in the field of organic synthesis. However, research on fluoroalkylthiocarbamates remains relatively limited, with slow development and significant shortcomings in their synthetic methods: existing reports generally suffer from problems such as single substrate structure, limited reaction sites, and a lack of types of fluoroalkylthio groups that can be introduced (mainly trifluoromethylthio), resulting in insufficient versatility as synthetic building blocks and greatly limiting their application in the construction of diverse molecules.

[0003] Meanwhile, pyrazole, as an important nitrogen-containing heterocyclic skeleton, has wide applications in pharmaceuticals, pesticides, and other fields, and the introduction of fluoroalkylthio groups can significantly improve its biological activity and metabolic stability. However, existing methods for synthesizing fluoroalkylthiopyrazoles usually require the prior preparation of pyrazole cores or thiophenol intermediates, which are lengthy and cumbersome, making it difficult to meet the needs of efficient and green synthesis. Summary of the Invention

[0004] To address the problems existing in the prior art, the purpose of this invention is to provide a fluoroalkylthio-ester ketone and its application in the synthesis of fluoroalkylthiopyrazoles. Bioactivity tests were conducted on the substrate fluoroalkylthio-ester ketone and the synthesized fluoroalkylthiopyrazole, revealing that this type of compound exhibits certain inhibitory activity against the growth of human endometrial adenocarcinoma cells (HEC-1-B) and human fibrosarcoma cells (HT-1080).

[0005] Specifically, the present invention is achieved through the following technical solution: In a first aspect, the present invention provides a fluoroalkylthio-enol ketone compound or a pharmaceutically acceptable salt thereof, its stereoisomers, solvates, polymorphs, tautomers, metabolites, or prodrugs, wherein the fluoroalkylthio-enol ketone compound has the structure shown in general formula I: (Ⅰ); Among them, R 1 Selected from acyl groups; R 2 Selected from one of ester, acyl, or amide groups; R f It is selected from one of monofluoroalkyl or difluoroalkyl.

[0006] A second aspect of the present invention provides a fluoroalkylthio-acetal ketone compound or a pharmaceutically acceptable salt thereof, its stereoisomers, solvates, polymorphs, tautomers, metabolites, or prodrugs, comprising the following steps: The β-dicarbonyl compound, basic catalyst and organic solvent were mixed, carbon disulfide was added at 0-5℃ and stirred until homogeneous, fluoroiodoalkane was added and stirred until homogeneous, then the mixture was raised to room temperature and stirred until the reaction was completed. After purification, the compound shown in general formula I was obtained. The structural formula of the β-dicarbonyl compound is as follows: , where R 4 and R 5 Each is independently selected from C1-C4 alkyl, C1-C4 alkoxy, phenyl, substituted phenyl or aniline groups; Fluoroiodoalkanes are selected from F-(CH2). x -I, x=1,2 and F2CH-CH2-I.

[0007] In a third aspect, the present invention provides the use of a fluoroalkylthiopyrazole compound or a pharmaceutically acceptable salt thereof, its stereoisomers, solvates, polymorphs, tautomers, metabolites or prodrugs in the preparation of a fluoroalkylthiopyrazole compound or a pharmaceutically acceptable salt thereof, its stereoisomers, solvates, polymorphs, tautomers, metabolites or prodrugs.

[0008] In a fourth aspect, the present invention provides a fluoroalkylthiopyrazole compound or a pharmaceutically acceptable salt thereof, its stereoisomers, solvates, polymorphs, tautomers, metabolites, or prodrugs, wherein the fluoroalkylthiopyrazole compound is shown in general formula II: (II) Among them, R 1 Selected from either ester or cyano groups; R 2 Selected from alkyl or aryl groups; R 3 Selected from either aryl or hydrogen atom; R f Selected from monofluoroalkyl groups.

[0009] In a fifth aspect, the present invention provides a method for preparing a fluoroalkylthiopyrazole compound or a pharmaceutically acceptable salt thereof, its stereoisomers, solvates, polymorphs, tautomers, metabolites or prodrugs, comprising: reacting a fluoroalkylthiopyrazole acetal with hydrazine to obtain a compound of general formula II.

[0010] In a sixth aspect, the present invention provides an anticancer drug comprising a fluoroalkylthio-pyrazole compound and a fluoroalkylthio-pyrazole compound or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, a polymorph thereof, a tautomer thereof, a metabolite thereof, or a prodrug.

[0011] One or more technical solutions of the present invention have the following beneficial effects: (1) The fluoroalkylthioenol compound provided by this invention retains the active methylene reaction site of ethyl acetoacetate while simultaneously introducing fluorine-containing and thioether structural units, significantly enhancing the structural novelty, potential biological activity, and functional group transformation potential of the product as an intermediate. Its preparation method uses inexpensive carbon disulfide as a sulfur bridging reagent, employing a one-pot tandem nucleophilic addition-alkylation reaction. Under mild conditions, it efficiently constructs CS bonds and introduces fluoroalkyl groups, offering advantages such as simple operation, rapid reaction, mild conditions, high atom economy, and no need for metal catalysts. This provides a practical route for the green synthesis of fluorine-containing thioether compounds.

[0012] (2) This invention also provides a method for synthesizing fluoroalkylthiopyrazole compounds. This method uses fluoroalkylthio acetals and hydrazine as substrates, reacting in an organic solvent without the need for metal reagents or base catalysis to obtain polysubstituted fluoroalkylthiopyrazole derivatives. Compared with existing technologies, this invention utilizes the reaction of fluoroalkylthio acetals with hydrazine to generate fluoroalkylthiopyrazole compounds. The preparation method of this invention is efficient, mild, simple to operate, and uses readily available raw materials and reagents, making it highly practical and suitable for synthesizing various fluoroalkylthiopyrazole derivatives.

[0013] (3) The fluoroalkylthio-pyrazole compounds synthesized in this invention have certain inhibitory activity on the growth of HEC-1-B and HT-1080. Attached Figure Description

[0014] The accompanying drawings, which form part of this specification, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. Hereinafter, embodiments of the invention will be described in detail with reference to the accompanying drawings, wherein: Figure 1 The 1H NMR spectrum of the fluoroalkylthio-enol ketone compound obtained in Example 1 of this invention; Figure 2 The NMR fluorine spectrum of the fluoroalkylthio-enol ketone compound obtained in Example 1 of this invention; Figure 3 The image shows the carbon NMR spectrum of the fluoroalkylthio-acetal ketone compound obtained in Example 1 of this invention.

[0015] Figure 4 The 1H NMR spectrum of the fluoroalkylthio-enol ketone compound obtained in Example 2 of this invention; Figure 5 The NMR fluorine spectrum of the fluoroalkylthio-enol ketone compound obtained in Example 2 of this invention; Figure 6 The image shows the carbon NMR spectrum of the fluoroalkylthio-acetal ketone compound obtained in Example 2 of this invention.

[0016] Figure 7 The 1H NMR spectrum of the fluoroalkylthio-enol ketone compound obtained in Example 3 of this invention; Figure 8 The NMR fluorine spectrum of the fluoroalkylthio-enol ketone compound obtained in Example 3 of this invention; Figure 9 The image shows the carbon NMR spectrum of the fluoroalkylthio-acetal ketone compound obtained in Example 3 of this invention.

[0017] Figure 10 The 1H NMR spectrum of the fluoroalkylthio-enol ketone compound obtained in Example 4 of this invention; Figure 11 The NMR fluorine spectrum of the fluoroalkylthio-enol compound obtained in Example 4 of this invention; Figure 12 The image shows the carbon NMR spectrum of the fluoroalkylthio-acetal ketone compound obtained in Example 4 of this invention.

[0018] Figure 13 The 1H NMR spectrum of the fluoroalkylthioenol compound obtained in Example 5 of this invention; Figure 14 The NMR fluorine spectrum of the fluoroalkylthio-enol ketone compound obtained in Example 5 of this invention; Figure 15 The image shows the carbon NMR spectrum of the fluoroalkylthio-acetal ketone compound obtained in Example 5 of this invention.

[0019] Figure 16 The 1H NMR spectrum of the fluoroalkylthio-enol ketone compound obtained in Example 6 of this invention; Figure 17 The NMR fluorine spectrum of the fluoroalkylthio-enol compound obtained in Example 6 of this invention; Figure 18 The image shows the carbon NMR spectrum of the fluoroalkylthio-acetal ketone compound obtained in Example 6 of this invention.

[0020] Figure 19 The 1H NMR spectrum of the fluoroalkylthioenol compound obtained in Example 7 of this invention; Figure 20 The NMR fluorine spectrum of the fluoroalkylthioenol compound obtained in Example 7 of this invention; Figure 21 The image shows the carbon NMR spectrum of the fluoroalkylthio-acetal ketone compound obtained in Example 7 of this invention.

[0021] Figure 22 The 1H NMR spectrum of the fluoroalkylthiopyrazole derivative obtained in Example 8 of this invention; Figure 23 The NMR fluorine spectrum of the fluoroalkylthiopyrazole derivative obtained in Example 8 of this invention; Figure 24 The image shows the carbon NMR spectrum of the fluoroalkylthiopyrazole derivative obtained in Example 8 of this invention.

[0022] Figure 25 The 1H NMR spectrum of the fluoroalkylthiopyrazole derivative obtained in Example 9 of this invention; Figure 26 The NMR fluorine spectrum of the fluoroalkylthiopyrazole derivative obtained in Example 9 of this invention; Figure 27 The image shows the carbon NMR spectrum of the fluoroalkylthiopyrazole derivative obtained in Example 9 of this invention.

[0023] Figure 28 The 1H NMR spectrum of the fluoroalkylthiopyrazole derivative obtained in Example 10 of this invention; Figure 29 The NMR fluorine spectrum of the fluoroalkylthiopyrazole derivative obtained in Example 10 of this invention; Figure 30 The image shows the carbon NMR spectrum of the fluoroalkylthiopyrazole derivative obtained in Example 10 of this invention.

[0024] Figure 31 The 1H NMR spectrum of the fluoroalkylthiopyrazole derivative obtained in Example 11 of this invention; Figure 32 The NMR fluorine spectrum of the fluoroalkylthiopyrazole derivative obtained in Example 11 of this invention; Figure 33 The image shows the carbon NMR spectrum of the fluoroalkylthiopyrazole derivative obtained in Example 11 of this invention. Detailed Implementation

[0025] The present invention will be 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 in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer. The purity and origin of the experimental reagents used in the present invention, as well as the model and origin of the experimental instruments, are shown in Tables 1 and 2, respectively.

[0026] Table 1 Experimental Apparatus

[0027] Table 2 Experimental Drugs and Reagents

[0028] In the following embodiments, the abbreviations have the following meanings: CDCl3: deuterated chloroform; DMSO-d6: deuterated DMSO; 1 HNMR: Proton nuclear magnetic resonance spectrum; 19 F NMR: Fluorine nuclear magnetic resonance spectrum; 13 C NMR: Carbon nuclear magnetic resonance spectrum; HRMS (ESI): High-resolution mass spectrometry (electrospray ionization); PE: Petroleum ether; EA: Ethyl acetate; DCM: Dichloromethane.

[0029] To address the common problems in existing methods for synthesizing fluoroalkylthiopyrazoles, such as reliance on metal reagents or strong base catalysis, stringent reaction conditions, complex operations, and insufficient environmental friendliness, this invention proposes a novel fluoroalkylthiopyrazole compound and its efficient and green synthetic method. This invention develops a metal-free, base-free, and mild synthetic strategy. Through cleverly designed reaction pathways, the fluoroalkylthiopyrazole skeleton is directly constructed under mild conditions. This not only avoids the cost and operational problems associated with using precious metal catalysts or strong bases, but also provides mild reaction conditions, simple operation, and environmental friendliness. Experiments show that the novel fluoroalkylthiopyrazole compound synthesized by this method exhibits certain inhibitory activity against the growth of HEC-1-B and HT-1080 cell lines, demonstrating its application potential in anti-tumor drug development.

[0030] Specifically, the present invention is achieved through the following technical solution: In a first aspect, the present invention provides a fluoroalkylthio-alkenyl ketone compound or a pharmaceutically acceptable salt thereof, its stereoisomers, solvates, polymorphs, tautomers, metabolites, or prodrugs, wherein the fluoroalkylthio-alkenyl ketone compound has the structure shown in general formula I: (Ⅰ); Among them, R 1 Selected from acyl groups; R 2 Selected from one of ester, acyl, or amide groups; R f It is selected from one of monofluoroalkyl or difluoroalkyl.

[0031] In one or more embodiments of the present invention, the R 1 Selected from acetyl or benzoyl; Furthermore, the R 2 Selected from one of ethyl ester group, acetyl group, phenylamido group or 4-chlorophenylamido group; Furthermore, the R f It is selected from one of monofluoromethyl, monofluoroethyl, or difluoroethyl.

[0032] In one or more embodiments of the present invention, Rf When selected from monofluoromethyl, R 1 Selected from acetyl or benzoyl, R 2 Selected from one of ethyl ester group, acetyl group, phenylamido group, or 4-chlorophenylamido group. R f When selected from difluoroethyl, R 1 Selected from acetyl, R 2 It is selected from either ethyl ester or acetyl groups.

[0033] In one or more embodiments of the present invention, the fluoroalkylthio-enol ketone compound comprises the following structure: .

[0034] A second aspect of the present invention provides a fluoroalkylthio-acetal ketone compound or a pharmaceutically acceptable salt thereof, its stereoisomers, solvates, polymorphs, tautomers, metabolites, or prodrugs, comprising the following steps: The β-dicarbonyl compound, basic catalyst and organic solvent were mixed, carbon disulfide was added at 0-5℃ and stirred until homogeneous, fluoroiodoalkane was added and stirred until homogeneous, then the mixture was raised to room temperature and stirred until the reaction was completed. After purification, the compound shown in general formula I was obtained. The structural formula of the β-dicarbonyl compound is as follows: , where R 4 and R 5 Each is independently selected from C1-C4 alkyl, C1-C4 alkoxy, phenyl, substituted phenyl or aniline groups; Fluoroiodoalkanes are selected from F-(CH2). x -I, x=1,2 and F2CH-CH2-I.

[0035] Further, the molar ratio of the alkaline catalyst to the β-dicarbonyl compound is (2-3):1; the molar ratio of the β-dicarbonyl compound to the fluoroiodoalkane is (2-3):1; the molar ratio of the β-dicarbonyl compound to carbon disulfide is 1:(1-1.5); the alkaline catalyst includes anhydrous potassium carbonate; Preferably, the β-dicarbonyl compound is selected from one of ethyl acetoacetate, acetylacetone, 2-benzoylacetanilide, and acetylacetyl-p-chloroaniline; Preferably, the fluoroiodoalkane is selected from one of 1-fluoro-2-iodoethane, fluoroiodomethane, 1,1-difluoro-2-iodoethane, and 1,1-difluoro-2-iodoethane.

[0036] In a third aspect, the present invention provides the use of a fluoroalkylthiopyrazole compound or a pharmaceutically acceptable salt thereof, its stereoisomers, solvates, polymorphs, tautomers, metabolites or prodrugs in the preparation of a fluoroalkylthiopyrazole compound or a pharmaceutically acceptable salt thereof, its stereoisomers, solvates, polymorphs, tautomers, metabolites or prodrugs.

[0037] In a fourth aspect, the present invention provides a fluoroalkylthiopyrazole compound or a pharmaceutically acceptable salt thereof, its stereoisomers, solvates, polymorphs, tautomers, metabolites, or prodrugs, wherein the fluoroalkylthiopyrazole compound has the structure shown in general formula II: (II) Among them, R 1 Selected from either ester or cyano groups; R 2 Selected from alkyl or aryl groups; R 3 Selected from either aryl or hydrogen atom; R f Selected from monofluoroalkyl groups.

[0038] In one or more embodiments of the present invention, the R 1 Selected from either ethyl ester group or cyano group; Furthermore, the R 2 Selected from methyl or phenyl; Furthermore, the R 3 Selected from 4-methylphenyl, 4-trifluoromethylphenyl, or hydrogen atom; Furthermore, the R f It is selected from one of monofluoromethyl or monofluoroethyl.

[0039] In one or more embodiments of the present invention, R f When selected from monofluoromethyl, R 1 Selected from either ethyl ester or cyano groups, R 2 Selected from one of methyl or phenyl, R 3 It is selected from 4-methylphenyl, 4-trifluoromethylphenyl, or hydrogen atom.

[0040] In one or more embodiments of the present invention, the fluoroalkylthiopyrazole compound comprises the following structure: .

[0041] In a fifth aspect, the present invention provides a method for preparing a fluoroalkylthiopyrazole compound or a pharmaceutically acceptable salt thereof, its stereoisomers, solvates, polymorphs, tautomers, metabolites or prodrugs, comprising: reacting a fluoroalkylthiopyrazole acetal with hydrazine to obtain a compound of general formula II.

[0042] Common strategies for synthesizing fluoroalkylthiopyrazoles involve reacting thiophenols with fluoroalkylating agents to construct fluoroalkylthiopyrazole compounds, or reacting heterocycles with fluoroalkylthioating agents to construct fluoroalkylthiopyrazole compounds. However, starting from the substrate can reduce the number of synthetic steps. Fluoroalkylthio ketal is a relatively unique organic compound with multiple reaction sites, giving it a unique advantage in the synthesis of nitrogen-containing heterocyclic compounds. Therefore, a new method for constructing fluoroalkylthiopyrazoles from fluorinated substrates was developed by reacting fluoroalkylthio ketal with hydrazine.

[0043] In one or more embodiments of the present invention, the reaction route is as follows:

[0044] Among them, R 1 R 2 R 3 R f The definition is as described above.

[0045] In one or more embodiments of the present invention, the preparation method includes: 1) In organic solvents, fluoroalkylthio-alkenyl acetals react with hydrazine; 2) After the reaction, the organic solvent was removed from the product, and then it was subjected to silica gel column chromatography to obtain the product shown in general formula II. compound (II) Furthermore, the hydrazine is selected from hydrazine hydrate, p-methylphenylhydrazine hydrochloride, or 4-trifluoromethylphenylhydrazine; Furthermore, the molar ratio of the fluoroalkylthio-acetal ketone to hydrazine is 1:1.2-2.0; more specifically, 1:2.0. When the molar ratio of the fluoroalkylthio-acetal ketone to hydrazine is 1:2.0, the product purity is higher.

[0046] Furthermore, the organic solvent is selected from tetrahydrofuran, acetonitrile, methanol, isopropanol or 1,4-dioxane; more specifically, it is tetrahydrofuran.

[0047] The type of solvent affects the mixing effect and product yield to a certain extent. Experiments have shown that the product yield is highest when the solvent is tetrahydrofuran.

[0048] Furthermore, for every 0.2 mmol of the fluoroalkylthio-alkenyl acetal, 2 mL of solvent needs to be added.

[0049] Furthermore, the reaction temperature is 60-100 ℃; further, the reaction temperature is 85 ℃.

[0050] This invention first provides a fluoroalkylthiopyrazole derivative, the general structural formula of which is shown in Formula II. Fluoroalkylthiopyrazole compounds are very important nitrogen-containing heterocyclic compounds with significant applications in the pharmaceutical and pesticide fields. Therefore, fluoroalkylthiopyrazole derivatives occupy a very important position in the fields of medicinal chemistry and organic synthesis.

[0051] This invention also provides a method for synthesizing fluoroalkylthiopyrazole derivatives. This method uses fluoroalkylthio acetals and hydrazine as substrates, reacting in an organic solvent without the need for metal reagents or base catalysis to obtain the fluoroalkylthiopyrazole derivatives. Compared with existing technologies, this invention utilizes the reaction of fluoroalkylthio acetals with hydrazine to generate fluoroalkylthiopyrazole compounds. The preparation method of this invention is efficient, mild, simple to operate, and uses readily available raw materials and reagents, making it highly practical and applicable to the synthesis of various fluoroalkylthiopyrazole derivatives.

[0052] In a sixth aspect, the present invention provides an anticancer drug comprising a fluoroalkylthio-pyrazole compound and a fluoroalkylthio-pyrazole compound or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a solvate thereof, a polymorph thereof, a tautomer thereof, a metabolite thereof, or a prodrug.

[0053] Preferably, the anticancer drug is a drug that inhibits the growth of HEC-1-B and HT-1080.

[0054] The present invention will be further described in detail below with reference to specific embodiments. It should be noted that the specific embodiments are explanations of the present invention and not limitations thereof.

[0055] Example 1 Preparation of compound 1a of general formula I

[0056] At room temperature, anhydrous potassium carbonate (0.44 mmol), ethyl acetoacetate 1a (0.2 mmol), and DMF 2 mL were added to a 25 mL round-bottom flask, followed by 0 mL of [presumably a flask name - likely a solution of DMF]. o Under C conditions, CS2 (0.24 mmol) was added dropwise and stirred for 0.5 h. Then, under ice bath and stirring conditions, fluoroiodomethane (0.44 mmol) was added dropwise to the reactor over approximately 5 min. Finally, the reaction mixture was stirred at room temperature for 1 h. After the reaction was complete as monitored by TLC, the reaction mixture was poured into ice water, diluted with dichloromethane, and then transferred to a separatory funnel for extraction with dichloromethane and saturated brine. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound 2a in 93% yield.

[0057] Figure 1 This is the hydrogen NMR spectrum obtained in Example 1 of the present invention. Figure 2 Its NMR fluorine spectrum. Figure 3 Its carbon NMR spectrum.

[0058] Spectral analysis data: 1 H NMR (400 MHz, CDCl3): δ 5.76 (d, J = 51.2 Hz, 2H), 5.73 (d, J = 51.2 Hz, 2H), 4.28 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). 19 F NMR (376MHz, CDCl3): δ -184.25, -185.28. 13 C NMR (100 MHz, CDCl3): δ 196.2, 163.4, 145.6(t, J = 3.4 Hz), 141.0 (t, J = 3.4 Hz), 86.8 (dd, J 1 = 219.4 Hz J 2 = 3.0 Hz), 86.3 (dd, J 1 = 219.4 Hz J 2= ​​3.0 Hz), 62.1, 30.1, 14.0. HRMS (ESI) m / z: [M+Na] + calcdfor C9H 12 F2NaO3S2 + 293.0088; found 293.0081. Example 2 Preparation of compound 2b of general formula I

[0059] By replacing ethyl acetoacetate 1a in Example 1 with acetylacetone 1b, and with other conditions the same as in Example 1, compound 2b was obtained in 93% yield.

[0060] Figure 4 This is the hydrogen NMR spectrum obtained in Example 2 of the present invention. Figure 5 Its NMR fluorine spectrum. Figure 6 Its carbon NMR spectrum.

[0061] Spectral analysis data: 1 H NMR (400 MHz, CDCl3): δ 5.71 (d, J = 51.2 Hz, 4H), 2.40 (s, 6H). 19 F NMR (376 MHz, CDCl3): δ -185.26. 13 C NMR (100 MHz, CDCl3): δ 197.4, 151.6 (t, J = 2.2Hz), 138.6 (t, J = 3.1 Hz), 86.1 (dd, J 1 = 219.2 Hz J 2= ​​2.2 Hz), 30.6. HRMS (ESI)m / z: [M+Na]+ calcd for C8H 10 F2NaO2S2 + 262.9982; found 262.9972. Example 3 Preparation of compound 2c of general formula I

[0062] By replacing ethyl acetoaniline 1a in Example 1 with 2-benzoylacetanilide 1c, and with other conditions the same as in Example 1, compound 2c was obtained in 75% yield.

[0063] Figure 7 This is the hydrogen NMR spectrum obtained in Example 3 of the present invention. Figure 8 Its NMR fluorine spectrum. Figure 9 Its carbon NMR spectrum.

[0064] Spectral analysis data: 1 H NMR (400 MHz, CDCl3): δ 8.23 (s, 1H), 8.04 (d, J = 7.6 Hz, 2H), 7.63(t, J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.31 (t, J =7.6 Hz, 2H), 7.12 (t, J= 7.6 Hz, 1H), 5.82 (d, J = 51.2 Hz, 2H), 5.58 (d, J = 51.2Hz, 2H). 19 F NMR (376 MHz, CDCl3): δ -184.00, -186.31. 13 C NMR (100 MHz, CDCl3): δ 193.0, 159.7, 145.7 (t, J = 2.3 Hz), 138.0 (t, J = 2.9 Hz), 136.9, 135.2, 134.6,129.9, 128.9, 128.8, 124.9, 119.8, 85.77 (d, J = 217.8 Hz), 85.75 (d, J = 218.7Hz). HRMS (ESI) m / z: [M+Na] + calcd for C 18 H 15 F2NNaO2S2 + 402.0404; 402.0400 was found. Example 4 Preparation of compound 2d of general formula I

[0065] Compound 2d was obtained by replacing ethyl acetoacetyl-p-chloroaniline 1d in Example 1 with acetyl-p-chloroaniline 1d, under the same conditions as in Example 1, with a yield of 88%.

[0066] Figure 10 This is the hydrogen NMR spectrum obtained in Example 4 of the present invention. Figure 11 Its NMR fluorine spectrum. Figure 12 Its carbon NMR spectrum.

[0067] Spectral analysis data: 1 H NMR (400 MHz, CDCl3): δ 8.20 (s, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.31(d, J = 8.0 Hz, 2H), 5.79 (d, J = 51.2 Hz, 2H), 5.76 (d,J = 51.2 Hz, 2H), 2.51 (s, 3H). 19 F NMR (376 MHz, CDCl3): δ -183.64, -185.07. 13 C NMR (100 MHz, CDCl3): δ 197.2, 161.9, 145.2, 142.7, 135.7, 130.1, 129.1, 121.2, 87.4 (dd, J 1 = 218.5Hz J 2 = 3.4 Hz), 85.5 (d, J = 218.6 Hz), 30.1. HRMS (ESI) m / z: [M+H] + calcd forC 13 H 13 ClF2NO2S2 + 352.0039; found 352.0040. Example 5 Preparation of compound 2e of general formula I

[0068] By replacing the fluoroiodomethyl 1 in Example 1 with 1-fluoro-2-iodoethane, and with other conditions the same as in Example 1, compound 2e was obtained in 94% yield.

[0069] Figure 13 This is the hydrogen NMR spectrum obtained in Example 6 of the present invention. Figure 14 Its NMR fluorine spectrum. Figure 15 Its carbon NMR spectrum.

[0070] Spectral analysis data: 1 H NMR (400 MHz, CDCl3): δ 4.53 (dt, J 1 = 46.8 Hz J 2 = 6.0 Hz, 4H), 4.26(q, J = 7.2 Hz, 2H), 3.23 (q, J = 6.0 Hz, 2H), 3.18 (q, J = 6.0 Hz, 2H), 2.35 (s,3H), 1.30 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, CDCl3): δ -213.93, -214.44. 13 C NMR (100 MHz, CDCl3): δ 195.6, 164.2, 149.1, 139.7, 81.23 (d, J = 171.6 Hz), 81.20 (d, J = 171.6 Hz) 61.8, 34.8 (d, J = 21.6 Hz), 34.7 (d, J = 21.8 Hz), 29.9, 13.9. HRMS(ESI) m / z: [M+Na] + calcd for C 11 H 16 F2NaO3S2 + 321.0401; found 321.0400. Example 6 Preparation of compound 2f of general formula I

[0071] By replacing the fluoroiodomethyl 1 in Example 1 with 1,1-difluoro-2-iodoethane, and with other conditions the same as in Example 1, compound 2f was obtained in 85% yield.

[0072] Figure 16 This is the hydrogen NMR spectrum obtained in Example 6 of the present invention. Figure 17 Its NMR fluorine spectrum. Figure 18 Its carbon NMR spectrum.

[0073] Spectral analysis data: 1 H NMR (400 MHz, CDCl3): δ 5.90 (tt, J 1 = 55.6 Hz J 2 = 4.0 Hz, 2H), 4.29(q, J = 7.2 Hz, 2H), 3.36–3.25 (m,4H), 2.37 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H). 19 FNMR (376 MHz, CDCl3): δ -114.88, -115.08. 13C NMR (100 MHz, CDCl3): δ 195.6, 163.6,146.5, 141.2, 114.3 (t, J = 241.7 Hz), 114.1 (t, J = 241.7 Hz), 62.1, 37.1 (t, J =24.9 Hz), 37.0 (t, J = 24.9 Hz), 29.8, 13.8. HRMS (ESI) m / z: [M+Na] + calcd forC 11 H 14 F4NaO3S2 + 357.0213; found 357.0209. Example 7 Preparation of 2g of compound of general formula I

[0074] By replacing the fluoroiodomethyl 1 in Example 1 with 1,1-difluoro-2-iodoethane, and replacing the ethyl acetoacetate 1a in Example 1 with acetylacetone 1b, and with other conditions the same as in Example 1, 2 g of the compound was obtained in a yield of 60%.

[0075] Figure 19 This is the hydrogen NMR spectrum obtained in Example 7 of the present invention. Figure 20 Its NMR fluorine spectrum. Figure 21 Its carbon NMR spectrum.

[0076] Spectral analysis data: 1 H NMR (400 MHz, CDCl3): δ 5.92 (tt, J 1 = 55.6 Hz J 2 = 3.6 Hz, 2H), 3.30(td, J 1 = 15.6 Hz J 2 = 3.6 Hz (4H), 2.43 (s, 6H). 19 F NMR (376 MHz, CDCl3): δ -115.20. 13 C NMR (100 MHz, CDCl3): δ 197.5, 151.1, 140.4, 114.0 (t, J = 231.6 Hz), 36.5 (t,J = 24.4 Hz), 30.4. HRMS (ESI) m / z: [M+H] + calcd for C 10 H 13 F4O2S2 + 305.0288; found 305.0284. Example 8 Preparation of compound 3a of general formula II

[0077] Add 2 h (0.2 mmol), hydrazine hydrate (0.4 mmol), and 2 mL of tetrahydrofuran to a 10 mL pressure-resistant tube. Add a stir bar, tighten the stopcock, and place the tube in a metal module preheated to 85 °C for heating. The reaction time is 4.5 h. After the reaction is complete as monitored by TLC, pour the reaction solution into ice water, dilute with dichloromethane, and then transfer to a separatory funnel for extraction with dichloromethane and water. The combined organic phases are dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound 3a in 78% yield.

[0078] Figure 22 The above is the hydrogen NMR spectrum obtained in Example 8 of this invention. Figure 23 Its NMR fluorine spectrum. Figure 24 Its carbon NMR spectrum.

[0079] Spectral analysis data: 1 H NMR (400 MHz, DMSO- d 6): δ 14.49 (s, 1H), 7.82 (d, J = 7.6 Hz, 2H),7.62–7.55 (m, 3H), 6.00 (d, J = 51.2 Hz, 2H). 19 F NMR (376 MHz, DMSO- d 6): δ -184.55. 13 C NMR (100 MHz, DMSO- d 6): δ 130.5, 129.4, 129.3, 126.5, 126.3, 114.3,113.9, 86.6 (d, J = 217.7 Hz).HRMS (ESI) m / z: [M+H] + calcd for C11 H9FN3S + 234.0496; found 234.0492. Example 9 Preparation of compound 3b of general formula II

[0080] By replacing 2h in Example 8 with 2f, and with other conditions the same as in Example 8, compound 3b was obtained in 92% yield.

[0081] Figure 25 This is the hydrogen NMR spectrum obtained in Example 9 of the present invention. Figure 26 Its NMR fluorine spectrum. Figure 27 Its carbon NMR spectrum.

[0082] Spectral analysis data: 1 H NMR (400 MHz, CDCl3): δ 10.66 (s, 1H), 4.66 (dt, J 1 = 47.2 Hz J 2 = 6.4Hz, 2H), 4.31 (q, J = 7.2 Hz, 2H), 3.42–3.34 (m, 2H), 2.51 (s, 3H), 1.36 (t, J =7.2 Hz, 3H). 19 F NMR (376 MHz, CDCl3): δ -211.09. 13 C NMR (100 MHz, CDCl3): δ 163.7,149.1, 146.2, 109.2, 82.0 (d, J = 169.4 Hz), 60.3, 30.0 (d, J = 22.2 Hz), 14.3,11.9. HRMS (ESI) m / z: [M+H] + calcd for C9H 14 FN2O2S + 233.0755; found 233.0745. Example 10 Preparation of compound 3c of general formula II

[0083] By replacing 2h in Example 8 with 2a and replacing hydrazine hydrate in Example 8 with 4-(trifluoromethyl)phenylhydrazine, and with other conditions the same as in Example 8, compound 3c was obtained with a yield of 47%.

[0084] Figure 28 This is the hydrogen NMR spectrum obtained in Example 10 of the present invention. Figure 29 Its NMR fluorine spectrum. Figure 30 Its carbon NMR spectrum.

[0085] Spectral analysis data: 1 H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 5.79 (d, J = 52.0 Hz, 2H), 4.37 (q, J = 7.2 Hz, 2H), 2.55 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H). 19 F NMR (376 MHz, CDCl3): δ -62.58, -186.47. 13 C NMR (100 MHz, CDCl3): δ 163.1, 152.8, 141.3, 136.2, 130.7 (q, J = 32.6 Hz), 129.5, 127.04,127.02, 126.0 (q, J = 3.7 Hz), 123.7 (q, J = 270.6 Hz), 117.0, 88.7 (d, J = 220.6Hz), 60.6, 14.7, 14.3. HRMS (ESI) m / z: [M+Na] + calcd for C 15 H 14 F4N2NaO2S + 385.0604; found 385.0602. Example 11 Preparation of compound 3d of general formula II

[0086] Using 2a instead of 2h in Example 8, and p-methylphenylhydrazine hydrochloride instead of hydrazine hydrate in Example 8, and adding NaOH (0.4 mmol), under the same conditions as in Example 8, compound 3d was obtained with a yield of 46%.

[0087] Figure 31 The above is the hydrogen NMR spectrum obtained in Example 11 of this invention. Figure 32 Its NMR fluorine spectrum. Figure 33 Its carbon NMR spectrum.

[0088] Spectral analysis data: 1 H NMR (400 MHz, CDCl3): δ 7.37 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 5.74 (d, J = 52.0 Hz, 2H), 4.36 (q, J = 7.2 Hz, 2H), 2.54 (s, 3H), 2.42 (s,3H), 1.40 (t, J = 7.2 Hz, 3H). 19 F NMR (376 MHz, CDCl3): δ -186.50. 13 C NMR (100MHz, CDCl3): δ 163.3, 152.0, 139.0, 136.0 (d, J = 3.2 Hz), 129.7, 129.4, 126.6,125.4, 115.7, 88.5 (d, J = 220.5 Hz), 60.4, 21.2, 14.7, 14.3. HRMS (ESI) m / z:[M+Na] + calcd for C 15 H 17 FN2NaO2S + 331.0887; found 331.0888. Performance Experiment: To investigate the bioactivity of fluoroalkylthiopyrazoles and fluoroalkylthiopyrazoles, the antitumor activities of the prepared compounds 2a-2g and 3a-3d against HEC-1-B and HT-1080 were determined using CCK-8 assay. The broad-spectrum antitumor drug 5-fluorouracil (5-FU) was used as a positive control.

[0089] As shown in Table 3, compounds 2a-2d, 3b, and 3d exhibit significant antitumor activity against HEC-1-B, with an IC50 value of [missing value]. 50 The value is relatively low. At the same time, it also shows a significant inhibitory effect on HT-1080, IC... 50 The values ​​were relatively low, indicating significant antitumor activity (Table 3). Compounds 2e, 2f, 2g, 3a, and 3c also showed inhibitory activity against the growth of HEC-1-B and HT-1080.

[0090] Table 3. Study on antitumor activity

[0091] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A fluoroalkylthio-enyl ketal compound, characterized in that, The fluoroalkylthioenol compound has the structure shown in general formula I: (Ⅰ)； Among them, R 1 Selected from acyl groups; R 2 Selected from one of ester, acyl, or amide groups; R f It is selected from one of monofluoroalkyl or difluoroalkyl.

2. The fluoroalkylthio-alkenyl ketal compound according to claim 1, characterized in that, R 1 Selected from acetyl or benzoyl; R 2 Selected from one of ethyl ester group, acetyl group, phenylamido group or 4-chlorophenylamido group; R f It is selected from one of monofluoromethyl, monofluoroethyl, or difluoroethyl.

3. The fluoroalkylthio-alkenyl ketal compound according to claim 1, characterized in that, R f When selected from monofluoromethyl, R 1 Selected from acetyl or benzoyl, R 2 Selected from one of ethyl ester group, acetyl group, phenylamido group or 4-chlorophenylamido group; Or, R f When selected from difluoroethyl, R 1 Selected from acetyl, R 2 Selected from either ethyl ester group or acetyl group; Preferably, the fluoroalkylthio-enol compound comprises the following structure: 。 4. A fluoroalkylthio-alkenyl ketal compound according to any one of claims 1-3, characterized in that, Includes the following steps: The β-dicarbonyl compound, basic catalyst and organic solvent were mixed, carbon disulfide was added at 0-5℃ and stirred until homogeneous, fluoroiodoalkane was added and stirred until homogeneous, then the mixture was raised to room temperature and stirred until the reaction was completed. After purification, the compound shown in general formula I was obtained. The structural formula of the β-dicarbonyl compound is as follows: , where R 4 and R 5 Each is independently selected from C1-C4 alkyl, C1-C4 alkoxy, phenyl, substituted phenyl or aniline groups; Fluoroiodoalkanes are selected from F-(CH2)xI, x=1,2 and F2CH-CH2-I.

5. The fluoroalkylthio-alkenyl ketal compound according to claim 4, characterized in that, The molar ratio of the alkaline catalyst to the β-dicarbonyl compound is (2-3):1; the molar ratio of the β-dicarbonyl compound to the fluoroiodoalkane is (2-3):1; the molar ratio of the β-dicarbonyl compound to carbon disulfide is 1:(1-1.5); the alkaline catalyst includes anhydrous potassium carbonate; Preferably, the β-dicarbonyl compound is selected from one of ethyl acetoacetate, acetylacetone, 2-benzoylacetanilide, and acetylacetyl-p-chloroaniline; Preferably, the fluoroiodoalkane is selected from one of 1-fluoro-2-iodoethane, fluoroiodomethane, 1,1-difluoro-2-iodoethane, and 1,1-difluoro-2-iodoethane.

6. The use of the fluoroalkylthio-acetal ketone compound according to any one of claims 1-3 in the preparation of fluoroalkylthio-pyrazole compounds.

7. A fluoroalkylthiopyrazole compound having the structure shown in general formula II: (Ⅱ) in, R 1 Selected from either ester or cyano groups; R 2 Selected from alkyl or aryl groups; R 3 Selected from either aryl or hydrogen atom; R f Selected from monofluoroalkyl groups.

8. The fluoroalkylthiopyrazole compound according to claim 7, characterized in that, R 1 Selected from either ethyl ester group or cyano group; R 2 Selected from methyl or phenyl; R 3 Selected from 4-methylphenyl, 4-trifluoromethylphenyl, or hydrogen atom; R f Selected from one of monofluoromethyl or monofluoroethyl; Preferably, R f When selected from monofluoromethyl, R 1 Selected from either ethyl ester or cyano groups, R 2 Selected from one of methyl or phenyl, R 3 Selected from 4-methylphenyl, 4-trifluoromethylphenyl, or hydrogen atom; More preferably, the fluoroalkylthiopyrazole compound comprises the following structure: 。 9. A method for preparing a fluoroalkylthiopyrazole compound, characterized in that, Includes the following steps: The fluoroalkylthio-acetal ketone according to any one of claims 1-3 is reacted with hydrazine to obtain the compound shown in general formula II.

10. An anticancer drug comprising the fluoroalkylthiopyrrolidone of any one of claims 1-3 as described in claim 1 and / or the fluoroalkylthiopyrazole compound of claim 7 or 8, and the corresponding pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, tautomer, metabolite, or prodrug; preferably, the anticancer drug is preferably a drug that inhibits the growth of HEC-1-B and HT-1080.

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