Thioamide derivative as well as synthesis method and application thereof

Abstract

The invention belongs to the technical field of organic compound process synthesis and application, and discloses a thioamide derivative and a synthesis method thereof. According to the preparation method, the gem-difluoroolefin which is simple and convenient to prepare and the cheap and abundant amine compound are used as raw materials, the green and economical sulfur salt is used as the vulcanizing reagent, and the thioamide derivative can be obtained at a relatively high yield by reacting in the organic solvent at a proper temperature; the structural formula of the thioamide derivative is # imgabs0. The synthesis method has the characteristics of simplicity and convenience in operation, mild conditions, greenness, economy and wide substrate compatibility, and solves the technical problem that the synthesis conditions of the thioamide derivative are complex and harsh. On one hand, the method is short in reaction period, can be amplified to gram scale, is insensitive to water and air, and is expected to be used for industrial production; on the other hand, the synthesis method is good in selectivity, can be efficiently used for modification of medicine molecules, and has a good application prospect in the field of medicine.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound process synthesis and applications, and particularly relates to a thioamide derivative, a synthesis method thereof, and applications thereof. Background Art

[0002] Thioamide derivatives are one of the important structural fragments of a variety of natural products and drug molecules. In the field of organic synthesis, such compounds are also general components for constructing thioheterocycles. At the same time, as bioisosteres of the amide bond, a large number of studies have shown that for certain specific active drug molecules, the replacement of the amide bond with a thioamide bond can greatly improve the chemical stability and biological activity of the drug molecule, such as antibacterial activity, anti-enzyme hydrolysis activity, etc. (A. Choudhary, R. T. Raines, ChemBioChem 2011, 12, 1801 - 1807; N. Mahanta, D. M. Szantai-Kis, E. J. Petersson, D. A. Mitchell, ACS Chem. Biol. 2019, 14, 142 - 163; D. Davyt, G. Serra, Mar. Drugs 2010, 8, 2755 - 2780; L. Kjaerulff, A. Sikandar, N. Zaburannyi, S. Adam, J. Herrmann, J. Koehnke, R. Müller, ACS Chem. Biol. 2017, 12, 2837 - 2841; J. Zhao, X. Jiang, Chin. Chem. Lett. 2018, 29, 1079 - 1087; N. A. Spiegelman, J. Y. Hong, J. Hu, H. Jing, M. Wang, I. R. Price, J. Cao, M. Yang, X. Y. Zhang, H. N. Lin, ChemMedChem 2019, 14, 744 - 748). Based on the important uses of thioamide derivatives, it is of great significance to synthesize such compounds by a simple and efficient method.Traditionally, synthetic thioamide compounds are commonly prepared by reacting amide compounds with sulfurizing reagents such as Lawesson's reagent or phosphorus pentasulfide through oxygen-sulfur exchange to construct thioamide bonds. However, such methods often require the use of excessive amounts of toxic sulfurizing reagents, have harsh reaction conditions, and poor reaction selectivity. In recent years, many studies on the preparation of thioamide derivatives using the Willgerodt-Kindler reaction have also been reported. Similarly, such reactions often require high-temperature reaction conditions and are substrate-limited. Recently, many methods for constructing thioamide derivatives using organic sulfides as sulfur sources have also been developed. However, in such methods, the sulfurizing reagent is prone to coordination with transition metals, which to a certain extent limits the application of such reactions (T. Ozturk, E. Ertas, O. Mert, Chem. Rev. 2007, 107, 5210-5278; D. L. Priebbenow, C. Bolm, Chem. Soc. Rev. 2013, 42, 7870-7880; X. Wang, M. Ji, S. Lim, H. Y. Jang, J. Org. Chem. 2014, 79, 7256-7260; B. Kurpil, B. Kumru, T. Heil, M. Antonietti, A. Savateev, Green Chem. 2018, 20, 838-842; C. Lu, X. Li, S. Chang, Y. Zhang, D. Xing, S. Wang, Y. Lin, H. Jiang, L. Huang, Org. Chem. Front. 2022, 9, 2382-2389; J. Yang, C. Wang, S. Xu, J. Zhao, Angew. Chem. Int. Ed. 2019, 58, 1382-1386; M. Saito, S. Murakami, T. Nanjo, Y. Kobayashi, Y. Takemoto, J. Am. Chem. Soc. 2020, 142, 8130-8135; Y. Liao, S. Zhang, X. Jiang, Angew. Chem. Int. Ed. 2023, 62, e202303625). Therefore, the development of a synthetic method for thioamide derivatives with mild conditions, green economy, simplicity, high efficiency, wide substrate scope, and good selectivity still needs to be further explored. Based on this goal, the present invention solves some technical problems in the synthesis of thioamide derivatives. Summary of the Invention

[0003] To solve the drawbacks and deficiencies of the prior art, the primary object of the present invention is to provide a method for synthesizing thioamide derivatives. The synthesis method of the present invention uses gem-difluoroalkenes with simple preparation and inexpensive and abundant amine compounds as raw materials, and green and economical thiosalts as sulfurizing reagents, and reacts in a suitable temperature and organic solvent to obtain thioamide derivatives in a relatively high yield. The synthesis method of the present invention has the characteristics of simple operation, mild conditions, green economy, and wide substrate compatibility, and solves the technical problem of complex and harsh synthesis conditions for thioamide derivatives. At the same time, the present invention can be used to modify amino acids and common drug molecules efficiently and with high selectivity, and has broad application prospects.

[0004] The second object of the present invention is to provide the thioamide derivatives prepared by the above synthesis method.

[0005] The third object of the present invention is to provide an application of thioamide derivatives.

[0006] The primary object of the present invention adopts the following technical scheme:

[0007] A method for synthesizing thioamide derivatives, comprising the following steps: mixing gem-difluoroalkenes, amine compounds, thiosalts and organic solvent I for reaction, and subjecting the obtained product to subsequent treatment to obtain thioamide derivatives; the molar ratio of the amine compound to the gem-difluoroalkene is 1:3 to 3:1, and the molar ratio of the amine compound to the thiosalt is 1:1 to 8; the gem-difluoroalkene is an aryl, substituted aryl, heteroaryl or substituted heteroaryl gem-difluoroalkene; the amine compound is a cyclic amine compound, a chain amine compound or an amino acid ester hydrochloride.

[0008] Preferably, the gem-difluoroolefin is one of phenyl gem-difluoroolefin, p-chlorophenyl gem-difluoroolefin, o-chlorophenyl gem-difluoroolefin, m-chlorophenyl gem-difluoroolefin, p-bromophenyl gem-difluoroolefin, p-fluorophenyl gem-difluoroolefin, m-nitrophenyl gem-difluoroolefin, p-methyl formate phenyl gem-difluoroolefin, p-methylsulfonyl phenyl gem-difluoroolefin, p-acetamido phenyl gem-difluoroolefin, p-phenyl phenyl gem-difluoroolefin, p-trifluoromethyl phenyl gem-difluoroolefin, p-morpholine phenyl gem-difluoroolefin, p-methoxy phenyl gem-difluoroolefin, 3,4,5-trichlorophenyl gem-difluoroolefin, p-methylthio phenyl gem-difluoroolefin, p-tert-butyl phenyl gem-difluoroolefin, m-cyano phenyl gem-difluoroolefin, o-methyl phenyl gem-difluoroolefin, m-methyl phenyl gem-difluoroolefin, p-methyl phenyl gem-difluoroolefin, 3,4-dimethoxy phenyl gem-difluoroolefin, 2-naphthalene gem-difluoroolefin, 1-naphthalene gem-difluoroolefin, 2-quinoline gem-difluoroolefin, 2-benzothiophene gem-difluoroolefin, 3-pyridyl, 3-indole gem-difluoroolefin, 5-(2-dimethylaminopyrimidine) gem-difluoroolefin, 4-(prop-2-yn-1-yloxy)phenyl gem-difluoroolefin, 2-(6,11-dihydro-11-oxodibenzo[b,e]oxepin) gem-difluoroolefin, 1,1-difluoro-2,2-distyrene.

[0009] Preferably, when the amine compound is a cyclic amine compound, the cyclic amine compound is one of pyrrolidine, piperidine, cyclohexylimine, tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, morpholine, thiomorpholine, N-phenylpiperazine, 8-chloro-11-(piperidin-4-ylidene)-6-11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, (3S,4R)-3-((benzo[d][1,3]dioxol-5-yloxymethyl)-4-(4-fluorophenyl)piperidine;

[0010] Or, when the amine compound is a linear amine compound, the linear amine compound is one of diethylamine, di-n-butylamine, dibenzylamine, aniline, n-butylamine, 2-methoxyethylamine, benzylamine, N-methylcyclopropylamine, N-methylallylamine, N-methylbenzylamine, N-methylaniline, N-methyl-γ-[4-(trifluoromethyl)phenoxy]amphetamine, phenylmethyl N-[(1S)-5-amino-1-[(phenylamino)carbonyl]pentyl]carbamate.

[0011] Or, when the amine compound is an amino acid ester hydrochloride, the amino acid ester hydrochloride is one of methyl glycinate hydrochloride, L-proline benzyl ester hydrochloride, L-leucine benzyl ester hydrochloride, L-isoleucine tert-butyl ester hydrochloride, L-alanine benzyl ester hydrochloride, L-methionine tert-butyl ester hydrochloride, L-phenylalanine tert-butyl ester hydrochloride, L-tryptophan methyl ester hydrochloride, L-valine tert-butyl ester hydrochloride, L-threonine tert-butyl ester hydrochloride, L-tyrosine tert-butyl ester hydrochloride, methyl 2-(2-aminoacetamido)acetate hydrochloride, (S)-2-amino-4-(methylthio)butanamide hydrochloride.

[0012] Preferably, the organic solvent I is at least one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, N-methylpyrrolidone, 1,4-dioxane.

[0013] Preferably, the sulfur salt is at least one of potassium sulfide, sodium sulfide, lithium sulfide.

[0014] Preferably, the reaction temperature is 25-120 °C, and the reaction time is 10 min-24 h; the reaction is carried out under an atmosphere of air, nitrogen or argon.

[0015] Preferably, the reaction temperature is 25 °C and the reaction time is 10 min.

[0016] Preferably, the molar ratio of the amine compound to the gem-difluoroolefin is 1:1.5-2; the molar ratio of the amine compound to the sulfur salt is 1:3-4. Preferably, the subsequent treatment refers to quenching the reaction, extracting the reaction solution with an organic solvent II, separating the aqueous layer, then drying the organic layer with a desiccant, filtering, and removing the organic solvent II by rotary evaporation under reduced pressure to obtain a crude product, which is purified by column chromatography to obtain a thioamide derivative.

[0017] Preferably, the quenching reaction is to add a saturated sodium chloride aqueous solution to the product; the organic solvent II is one of ethyl acetate or dichloromethane; the desiccant is at least one of anhydrous sodium sulfate or anhydrous magnesium sulfate.

[0018] Preferably, the column chromatography purification refers to mixing petroleum ether and ethyl acetate in a volume ratio of 1:5-500:1 as the eluent for column chromatography purification.

[0019] Preferably, the column chromatography purification refers to mixing petroleum ether and ethyl acetate in a volume ratio of 1:2-100:1 as the eluent for column chromatography purification.

[0020] The second object of the present invention adopts the following technical scheme:

[0021] A thioamide derivative is prepared by the above synthesis method.

[0022] Preferably, the thioamide derivative has the following structure:

[0023]

[0024] Wherein, R 1 is one of phenyl, p-chlorophenyl, o-chlorophenyl, m-chlorophenyl, p-bromophenyl, p-fluorophenyl, m-nitrophenyl, p-methoxycarbonylphenyl, p-methylsulfonylphenyl, p-acetamidophenyl, p-phenylphenyl, p-trifluoromethylphenyl, p-morpholinophenyl, p-methoxyphenyl, 3,4,5-trichlorophenyl, p-methylthiophenyl, p-tert-butylphenyl, m-cyanophenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, 3,4-dimethoxyphenyl, 2-naphthyl, 1-naphthyl, 2-quinolyl, 2-benzothienyl, 3-pyridyl, 3-indolyl, 5-(2-dimethylaminopyrimidine)yl, 4-(prop-2-yn-1-yloxy)phenyl, 2-(6,11-dihydro-11-oxodibenzo[b,e]oxepin)yl;

[0025] Said R 2 is one of hydrogen or phenyl;

[0026] R 3 / R 4 is one of ethyl / ethyl, n-butyl / n-butyl, benzyl / benzyl, hydrogen / phenyl, hydrogen / n-butyl, hydrogen / 2-methoxyethyl, hydrogen / benzyl, methyl / cyclopropyl, methyl / allyl, methyl / benzyl, methyl / γ-[4-(trifluoromethyl)phenoxy]phenylpropyl, hydrogen / phenylmethyl N-[(1S)-5-amino-1-[(phenylamino)carbonyl]pentyl]carbamate;

[0027] The third object of the present invention adopts the following technical scheme:

[0028] Use of a thioamide derivative in the field of medicine.

[0029] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0030] (1) The raw materials used in the synthesis method of the present invention are cheap and easily available, the sulfur source (sulfur salt) used is green and environmentally friendly, no metal and catalyst are required, the reaction period is short, the product purification is simple, the functional group compatibility is good, and the product yield is high;

[0031] (2) The synthesis method of the present invention can be scaled up to gram-scale or larger-scale production, and the operation is simple and safe, the reaction conditions are mild, and it is insensitive to water and air, and is expected to be used in industrial large-scale production;

[0032] (3) The synthesis method of the present invention has good selectivity, can be efficiently used for the modification of amino acids, polypeptides and drug molecules, and has good application prospects in the field of medicine. Description of the Drawings

[0033] Figure 1 1H NMR spectra of the thioamide derivatives obtained in Examples 1 - 5;

[0034] Figure 2 13C NMR spectra of the thioamide derivatives obtained in Examples 1 - 5. Detailed Description of the Invention

[0035] The present invention will be further described in detail below in conjunction with the examples and the drawings, but the implementation manners of the present invention are not limited thereto. For the process parameters not specifically noted, conventional techniques can be referred to.

[0036] Example 1

[0037] This example provides a thioamide derivative and its preparation method.

[0038] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.6 mmol of sodium sulfide, 0.3 mmol of hexahydropyridine, 2 mL of N - methylpyrrolidone, and 0.2 mmol of 4 - chlorophenyl gem - difluoroolefin were added to a 25 - mL graduated tube. The reaction system was stirred at 25 °C for 10 minutes, then the stirring was stopped, and the reaction was quenched by adding saturated sodium chloride aqueous solution. The reaction solution was extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it was separated and purified by column chromatography. The column chromatography eluent used was petroleum ether and ethyl acetate with a volume ratio of 10:1; the yield of the product was 66%.

[0039] Example 2

[0040] This example provides a thioamide derivative and its preparation method.

[0041] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.6 mmol of sodium sulfide, 0.3 mmol of hexahydropyridine, 2 mL of acetonitrile, and 0.2 mmol of 4 - chlorophenyl gem - difluoroolefin were added to a 25 - mL graduated tube. The reaction system was stirred at 25 °C for 10 minutes, then the stirring was stopped, and the reaction was quenched by adding saturated sodium chloride aqueous solution. The reaction solution was extracted with ethyl acetate, and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it was separated and purified by column chromatography. The column chromatography eluent used was petroleum ether and ethyl acetate with a volume ratio of 10:1; the yield of the product was 72%.

[0042] Example 3

[0043] This example provides a thioamide derivative and its preparation method.

[0044] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.6 mmol of sodium sulfide, 0.3 mmol of piperidine, 2 mL of N,N-dimethylformamide, and 0.2 mmol of 4-chlorophenyl gem-difluoroolefin are added to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, the stirring is stopped, the reaction is quenched by adding saturated sodium chloride aqueous solution, the reaction solution is extracted with ethyl acetate, the ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography to obtain the target product. The eluent used for column chromatography is petroleum ether and ethyl acetate with a volume ratio of 10:1; the yield of the product is 71%.

[0045] Example 4

[0046] This example provides a thioamide derivative and a preparation method thereof.

[0047] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.6 mmol of sodium sulfide, 0.2 mmol of piperidine, 2 mL of dimethyl sulfoxide, and 0.3 mmol of 4-chlorophenyl gem-difluoroolefin are added to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, the stirring is stopped, the reaction is quenched by adding saturated sodium chloride aqueous solution, the reaction solution is extracted with ethyl acetate, the ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography to obtain the target product. The eluent used for column chromatography is petroleum ether and ethyl acetate with a volume ratio of 10:1; the yield of the product is 94%.

[0048] Example 5

[0049] This example provides a thioamide derivative and a preparation method thereof.

[0050] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.6 mmol of lithium sulfide, 0.2 mmol of piperidine, 2 mL of dimethyl sulfoxide, and 0.3 mmol of 4-chlorophenyl gem-difluoroolefin are added to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, the stirring is stopped, the reaction is quenched by adding saturated sodium chloride aqueous solution, the reaction solution is extracted with ethyl acetate, the ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography to obtain the target product. The eluent used for column chromatography is petroleum ether and ethyl acetate with a volume ratio of 10:1; the yield of the product is 93%.

[0051] The same thioamide derivative is prepared in Examples 1 to 5.

[0052] The hydrogen spectrum and carbon spectrum of the obtained product are respectively as Figure 1 and Figure 2 shown; the structural characterization data are as follows:[[]]END]]

[0053] 1 H NMR(400 MHz, CDCl3) δ 7.29 (s, 4H), 4.29 (s, 2H), 4.28 - 4.23 (m, 2H), 3.59 - 3.53 (m, 2H), 1.68 - 1.60 (m, 4H), 1.33 (p, J=6.2 Hz, 2H);

[0054] 13 C NMR(101 MHz, CDCl3) δ 197.5, 134.7, 132.6, 129.3, 128.8, 51.6, 51.6, 50.0, 26.3, 25.3, 23.8.

[0055] Based on the above data, deduce the structure of the obtained product:

[0056]

[0057] Example 6

[0058] This example provides a thioamide derivative and a preparation method thereof.

[0059] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, add 0.6 mmol of sodium sulfide, 0.2 mmol of hexahydropyridine, 2 mL of dimethyl sulfoxide, and 0.3 mmol of 4-(methylthio)phenyl gem-difluoroolefin to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, then the stirring is stopped, and the reaction is quenched by adding a saturated sodium chloride aqueous solution. The reaction solution is extracted with ethyl acetate, and the ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography, and the target product is obtained. The eluent used for column chromatography is petroleum ether and ethyl acetate with a volume ratio of 12:1; the yield of the product is 81%.

[0060] The structure characterization data of the product obtained in this example are as follows:

[0061] 1 H NMR(400 MHz, CDCl3) δ 7.31 - 7.12 (m, 4H), 4.29 (s, 2H), 4.25 (t, J=5.3 Hz, 2H), 3.63 - 3.52 (m, 2H), 2.46 (s, 3H), 1.63 (q, J=8.0, 6.8 Hz, 4H), 1.37 - 1.27 (m, 2H);

[0062] 1313C NMR (101 MHz, CDCl3) δ 198.1, 136.9, 133.0, 128.4, 127.0, 51.6, 51.6, 50.3, 26.3, 25.3, 23.8, 15.9;

[0063] IR (KBr): 2932, 2860, 1629, 1492, 1442, 1243, 1033, 920 cm -1 ;

[0064] HRMS (APCI, m / z): [M+H] + Calcd. for C 14 H 19 NS2+H, 266.1032; found, 266.1036.

[0065] Based on the above data, the structure of the obtained product was deduced:

[0066]

[0067] Example 7

[0068] This example provides a thioamide derivative and its preparation method.

[0069] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.6 mmol of sodium sulfide, 0.2 mmol of piperidine, 2 mL of dimethyl sulfoxide, and 0.3 mmol of 3-cyanophenyl gem-difluoroolefin were added to a 25-mL graduated tube. The reaction system was stirred at 25 °C for 10 minutes, the stirring was stopped, the reaction was quenched with saturated sodium chloride aqueous solution, the reaction solution was extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it was separated and purified by column chromatography to obtain the target product. The eluent used for column chromatography was petroleum ether and ethyl acetate with a volume ratio of 4:1; the yield of the product was 75%.

[0070] The structure characterization data of the product obtained in this example are as follows:

[0071] 1 1H NMR (400 MHz, CDCl3) δ 7.65 - 7.57 (m, 2H), 7.53 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.7 Hz, 1H), 4.32 (s, 2H), 4.25 (t, J = 5.2 Hz, 2H), 3.60 - 3.53 (m, 2H), 1.71 - 1.58 (m, 4H), 1.37 (p, J = 5.6 Hz, 2H);

[0072] 1313C NMR (101 MHz, CDCl3) δ 196.6, 137.9, 132.7, 131.6, 130.7, 129.6, 118.6, 112.7, 51.7, 49.7, 26.5, 25.3, 23.8;

[0073] IR (KBr): 2937, 2860, 2230, 1495, 1446, 1261, 1088, 956, 902, 855, 798, 693, 569, 493, 451 cm -1 ;

[0074] HRMS (APCI, m / z): [M + H] + Calcd. for C 14 H 16 N2S + H, 245.1107; found, 245.1110.

[0075] Based on the above data, the structure of the obtained product is deduced as follows:

[0076]

[0077] Example 8

[0078] This example provides a thioamide derivative and its preparation method.

[0079] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.6 mmol of sodium sulfide, 0.2 mmol of hexahydropyridine, 2 mL of dimethyl sulfoxide, and 0.3 mmol of 2-benzothiophene gem-difluoroolefin were added to a 25-mL graduated tube. The reaction system was stirred at 25 °C for 10 minutes, the stirring was stopped, the reaction was quenched with saturated sodium chloride aqueous solution, the reaction solution was extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. The target product was obtained by column chromatography separation and purification. The eluent used for column chromatography was petroleum ether and ethyl acetate with a volume ratio of 10:1; the yield of the product was 76%.

[0080] The structure characterization data of the product obtained in this example are as follows:

[0081] 1 1H NMR (400 MHz, CDCl3) δ 7.84 (dd, J = 32.4, 7.8 Hz, 2H), 7.48 - 7.35 (m, 2H), 7.29 (s, 1H), 4.50 (s, 2H), 4.40 - 4.26 (m, 2H), 3.60 - 3.46 (m, 2H), 1.77 - 1.61 (m, 4H), 1.38 (p, J = 5.8 Hz, 2H);

[0082] 13 13C NMR (101 MHz, CDCl3) δ 197.5, 140.4, 138.0, 130.3, 124.7, 124.3, 123.0, 122.9, 121.3, 51.8, 51.5, 44.6, 26.5, 25.4, 23.8;

[0083] IR (KBr): 2932, 2857, 1493, 1440, 1262, 1126, 1076, 1015, 950, 857, 756 cm -1 ;

[0084] HRMS (APCI, m / z): [M+H] + Calcd. for C 15 H 17 NS2 + H, 276.0875; found, 276.0880.

[0085] The structure of the product inferred from the above data is as follows:

[0086]

[0087] Example 9

[0088] This example provides a thioamide derivative and a preparation method thereof.

[0089] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.6 mmol of sodium sulfide, 0.2 mmol of hexahydropyridine, 2 mL of dimethyl sulfoxide, and 0.3 mmol of 2-(methoxycarbonyl)-1H-indole-3-difluorovinylene are added to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, then the stirring is stopped, and the reaction is quenched by adding saturated sodium chloride aqueous solution. The reaction solution is extracted with ethyl acetate. The ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography. The eluent used for column chromatography is petroleum ether and ethyl acetate with a volume ratio of 3:1; the yield of the product is 68%.

[0090] The structure characterization data of the product obtained in this example are as follows:

[0091] 11H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.40 - 7.23 (m, 3H), 4.34 (s, 2H), 4.31 (t, J = 5.6 Hz, 2H), 3.59 (t, J = 5.3 Hz, 2H), 2.59 (s, 3H), 1.74 - 1.58 (m, 4H), 1.43 (t, J = 5.8 Hz, 2H);

[0092] 13 13C NMR (101 MHz, CDCl3) δ 197.4, 168.5, 135.7, 129.6, 125.7, 123.7, 122.8, 118.6, 117.5, 116.7, 51.7, 51.6, 41.0, 26.7, 25.4, 24.1, 23.8;

[0093] IR (KBr): 2934, 2860, 1704, 1496, 1448, 1380, 1340, 1254, 1014, 941, 859, 753, 663, 630 cm -1 ;

[0094] HRMS (APCI, m / z): [M + H] + Calcd. for C 17 H 20 N2O2S + H, 315.1173; found, 315.1177.

[0095] Based on the above data, deduce the structure of the obtained product:

[0096]

[0097] Example 10

[0098] This example provides a thioamide derivative and its preparation method.

[0099] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.6 mmol of sodium sulfide, 0.2 mmol of piperidine, 2 mL of dimethyl sulfoxide, and 0.3 mmol of 6,11-dihydro-11-oxodibenzo[b,e]oxepin-2-carboxaldehyde difluoromethylene were added to a 25-mL graduated tube. The reaction system was stirred at 25 °C for 10 minutes, the stirring was stopped, and the reaction was quenched by adding a saturated aqueous sodium chloride solution. Ethyl acetate was added to extract the reaction solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it was separated and purified by column chromatography. The eluent used for column chromatography was petroleum ether and ethyl acetate with a volume ratio of 3:1; the yield of the product was 82%. The structural characterization data of the product obtained in this example are as follows:

[0100] 1 H NMR(400MHz,CDCl3)δ8.07(s,1H),7.88(d,J=7.6Hz,1H),7.64-7.51(m,2H),7.49-7.33(m,2H),7.02(d,J=8.5Hz,1H),5.17(s,2H),4.32(s,2H),4.27(t,J=5.3Hz,2H),3.63(t,J=5.6Hz,2H),1.72-1.58(m,4H),1.40(q,J=5.7Hz,2H);

[0101] 13 C NMR(101MHz,CDCl3)δ197.9,190.7,160.3,140.3,135.6,135.1,132.9,131.0,130.0,129.5,129.3,127.9,125.2,121.3,73.7,51.7,51.6,49.6,26.4,25.3,23.9;

[0102] IR(KBr):2932,2859,1648,1600,1491,1448,1295,1128,1013,828,757,635cm -1 ;

[0103] HRMS(APCI,m / z):[M+H] + Calcd.for C 21 H 21 NO2S+H,352.1366;found,352.1371.

[0104] Deduce the structure of the product based on the above data:

[0105]

[0106] Example 11

[0107] This example provides a thioamide derivative and its preparation method.

[0108] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.6 mmol of sodium sulfide, 0.2 mmol of hexahydropyridine, 2 mL of dimethyl sulfoxide, and 0.3 mmol of 6-methoxy-3-pyridyl gem-difluoroolefin are added to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, then the stirring is stopped, and the reaction is quenched by adding a saturated sodium chloride aqueous solution. The reaction solution is extracted with ethyl acetate, and the ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography to obtain the target product. The eluent used for column chromatography is petroleum ether and ethyl acetate with a volume ratio of 12:1; the yield of the product is 79%.

[0109] The structure characterization data of the product obtained in this example are as follows:

[0110] 1 H NMR(400MHz,CDCl3)δ8.03(d,J=2.8Hz,1H),7.69(dd,J=8.6,2.5Hz,1H),6.70(d,J=8.6Hz,1H),4.24(t,J=5.2Hz,2H),4.21(s,2H),3.90(s,3H),3.65-3.58(m,2H),1.69-1.58(m,4H),1.39(q,J=5.7Hz,2H);

[0111] 13 C NMR(101MHz,CDCl3)δ197.8,163.3,145.9,138.5,124.6,111.0,53.4,51.7,51.5,46.9,26.5,25.2,23.8;

[0112] IR(KBr):2935,2848,1601,1568,1491,1448,1386,1282,1125,1019,828,758cm -1 ;

[0113] HRMS(APCI,m / z):[M+H] + Calcd.for C 13 H 18 N2OS+H,251.1213;found,251.1215.

[0114] Based on the above data, the structure of the obtained product is deduced:

[0115]

[0116] Example 12

[0117] This example provides a thioamide derivative and a preparation method thereof.

[0118] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.6 mmol of sodium sulfide, 0.2 mmol of N-allylmethylamine, 2 mL of dimethyl sulfoxide, and 0.3 mmol of 4-chlorophenyl gem-difluoroolefin are added to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, the stirring is stopped, the reaction is quenched by adding a saturated sodium chloride aqueous solution, the reaction solution is extracted with ethyl acetate, the ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography to obtain the target product. The column chromatography eluent used is petroleum ether and ethyl acetate with a volume ratio of 10:1; the yield of the product is 77%.

[0119] The structure characterization data of the product obtained in this example are as follows:

[0120] 1 H NMR(400MHz,CDCl3)δ7.28(dd,J=5.3,1.7Hz,4H),5.91-5.50(m,1H),5.28-5.07(m,2H),4.65(d,J=5.8Hz,1H),4.24(d,J=10.4Hz,2H),4.11-4.09(m,1H),3.26(d,J=125.9Hz,3H);

[0121] 13 C NMR(101MHz,CDCl3)δ200.5,200.4,134.7,134.2,132.8,130.6,130.3,129.6,129.6,128.9,128.9,118.7,118.3,58.3,56.8,50.2,49.4,42.7,39.4;

[0122] IR(KBr):3074,2926,1495,1400,1268,1094,1006,929,806,755,560,491cm -1 ;

[0123] HRMS(APCI,m / z):[M+H] + Calcd.for C 12 H 14 ClNS+H,240.0608;found,240.0611.

[0124] Infer the structure of the product based on the above data:

[0125]

[0126] Example 13

[0127] This example provides a thioamide derivative and a preparation method thereof.

[0128] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, add 0.6 mmol of sodium sulfide, 0.2 mmol of N-phenylpiperazine, 2 mL of dimethyl sulfoxide, and 0.3 mmol of 4-chlorophenyl gem-difluoroolefin to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, then the stirring is stopped, and the reaction is quenched by adding a saturated sodium chloride aqueous solution. The reaction solution is extracted with ethyl acetate, and the ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography to obtain the target product. The eluent used for column chromatography is petroleum ether and ethyl acetate with a volume ratio of 8:1; the yield of the product is 84%.

[0129] The structure characterization data of the product obtained in this example are as follows:

[0130] 1 H NMR(400MHz,CDCl3)δ7.35 - 7.24(m,6H),6.93(t,J=7.3Hz,1H),6.88(d,J=7.9Hz,2H),4.53 - 4.44(m,2H),4.37(s,2H),3.80(t,J=5.2Hz,2H),3.29(t,J=5.2Hz,2H),3.05 - 2.95(m,2H);

[0131] 13 C NMR(101MHz,CDCl3)δ199.2,150.1,134.4,133.0,129.4,129.3,129.1,120.7,116.4,50.0,50.0,49.7,49.2,48.4;

[0132] IR(KBr):3030,2915,2825,1594,1492,1442,1288,1229,1154,1095,1022,964,804,755,690,487cm -1 ;

[0133] HRMS(APCI,m / z):[M + H] + Calcd.for C 18 H 19ClN2S+H, 331.1030; found, 331.1034.

[0134] Based on the above data, deduce the structure of the product:

[0135]

[0136] Example 14

[0137] This example provides a thioamide derivative and a preparation method thereof.

[0138] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, add 0.6 mmol of sodium sulfide, 0.2 mmol of cyclohexylimine, 2 mL of dimethyl sulfoxide, and 0.3 mmol of 4-chlorophenyl gem-difluoroolefin to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, the stirring is stopped, the reaction is quenched by adding saturated sodium chloride aqueous solution, the reaction solution is extracted with ethyl acetate, the ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography to obtain the target product. The eluent used for column chromatography is petroleum ether and ethyl acetate with a volume ratio of 10:1; the yield of the product is 81%.

[0139] The structure characterization data of the product obtained in this example are as follows:

[0140] 1 H NMR (400 MHz, CDCl3) δ 7.34 - 7.14 (m, 4H), 4.23 (s, 2H), 4.09 (t, J = 6.0 Hz, 2H), 3.60 (t, J = 6.0 Hz, 2H), 1.86 (p, J = 6.1 Hz, 2H), 1.60 - 1.41 (m, 6H);

[0141] 13 C NMR (101 MHz, CDCl3) δ 198.9, 134.8, 132.6, 129.6, 128.8, 54.5, 53.0, 49.9, 28.5, 27.0, 26.0, 25.3;

[0142] IR (KBr): 2930, 2858, 1495, 1445, 1296, 1189, 1096, 1014, 807, 754, 673, 487 cm -1 ;

[0143] HRMS (APCI, m / z): [M + H] + Calcd. for C 14 H 18 ClNS + H, 268.0921; found, 268.0924.

[0144] Infer the structure of the product based on the above data:

[0145]

[0146] Example 15

[0147] This example provides a thioamide derivative and its preparation method.

[0148] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, add 0.6 mmol of sodium sulfide, 0.2 mmol of aniline, 2 mL of dimethyl sulfoxide, and 0.4 mmol of 4-chlorophenyl gem-difluoroolefin to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, then the stirring is stopped, and the reaction is quenched by adding a saturated sodium chloride aqueous solution. The reaction solution is extracted with ethyl acetate, and the ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography to obtain the target product. The eluent used for column chromatography is petroleum ether and ethyl acetate with a volume ratio of 5:1; the yield of the product is 57%.

[0149] The structure characterization data of the product obtained in this example are as follows:

[0150] 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),7.82(d,J=7.9Hz,2H),7.51-7.36(m,6H),7.24(t,J=7.4Hz,1H),4.11(s,2H);

[0151] 13 C NMR(101MHz,DMSO-d6)δ200.9,139.9,137.1,132.0,131.1,129.0,128.7,126.6,123.7,52.7;

[0152] IR(KBr):3178,2968,1491,1402,1123,1015,769,705,576,494cm -1 ;

[0153] HRMS(APCI,m / z):[M+H] + Calcd.for C 14 H 12 ClNS+H,262.0452;found,262.0456.

[0154] Infer the structure of the product based on the above data:

[0155]

[0156] Example 16

[0157] This example provides a thioamide derivative and a preparation method thereof.

[0158] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.6 mmol of sodium sulfide, 0.2 mmol of 2-methoxyethylamine, 2 mL of dimethyl sulfoxide, and 0.4 mmol of 4-chlorophenyl gem-difluoroolefin are added to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, the stirring is stopped, the reaction is quenched by adding a saturated sodium chloride aqueous solution, the reaction solution is extracted with ethyl acetate, the ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography to obtain the target product. The eluent used for column chromatography is petroleum ether and ethyl acetate with a volume ratio of 3:1; the yield of the product is 70%.

[0159] The structure characterization data of the product obtained in this example are as follows:

[0160] 1 H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.32 - 7.16 (m, 4H), 4.00 (s, 2H), 3.78 (q, J = 5.0 Hz, 2H), 3.50 (t, J = 5.1 Hz, 2H), 3.26 (s, 3H);

[0161] 13 C NMR (101 MHz, CDCl3) δ 201.8, 134.1, 133.4, 130.6, 129.0, 69.3, 58.8, 52.1, 45.8;

[0162] IR (KBr): 3251, 3049, 2929, 1533, 1410, 1336, 1281, 1113, 819, 742, 690, 493 cm -1 ;

[0163] HRMS (APCI, m / z): [M + H] + Calcd. for C 11 H 14 ClNS + H, 244.0557; found, 244.0560.

[0164] Based on the above data, the structure of the obtained product is deduced:

[0165]

[0166] Example 17

[0167] This example provides a thioamide derivative and a preparation method thereof.

[0168] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.6 mmol of sodium sulfide, 0.2 mmol of phenethylamine, 2 mL of dimethyl sulfoxide, and 0.4 mmol of 4-chlorophenyl gem-difluoroolefin are added to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, the stirring is stopped, the reaction is quenched by adding saturated sodium chloride aqueous solution, the reaction solution is extracted with ethyl acetate, the ethyl acetate layer is dried with anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography to obtain the target product. The eluent used for column chromatography is petroleum ether and ethyl acetate with a volume ratio of 10:1; the yield of the product is 89%.

[0169] The structure characterization data of the product obtained in this example are as follows:

[0170] 1 H NMR(400MHz,CDCl3)δ7.45(s,1H),7.37 - 7.32(m,5H),7.27 - 7.15(m,4H),4.82(d,J=5.4Hz,2H),4.08(s,2H);

[0171] 13 C NMR(101MHz,CDCl3)δ201.7,135.9,133.7,133.7,130.7,129.3,129.0,128.1,128.0,52.2,50.3;

[0172] IR(KBr):3180,3037,2992,2948,1765,1542,1444,1416,1333,1244,1118,1083,956,902,750,693,594,537,494cm -1 ;

[0173] HRMS(APCI,m / z):[M + H] + Calcd.for C 15 H 14 ClNS + H,276.0608;found,276.0611.

[0174] Based on the above data, the structure of the obtained product is deduced:

[0175]

[0176] Example 18

[0177] This example provides a thioamide derivative and its preparation method.

[0178] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, add 0.8 mmol of sodium sulfide, 0.2 mmol of glycine methyl ester hydrochloride, 2 mL of dimethyl sulfoxide, and 0.4 mmol of 4-chlorophenyl gem-difluoroolefin to a 25 mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, then the stirring is stopped, and the reaction is quenched by adding saturated sodium chloride aqueous solution. Ethyl acetate is added to extract the reaction solution. The ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography. The column chromatography eluent used is petroleum ether and ethyl acetate with a volume ratio of 2:1; the yield of the product is 61%.

[0179] The structure characterization data of the product obtained in this example are as follows:

[0180] 1 H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 4.37 (d, J = 4.7 Hz, 2H), 4.11 (s, 2H), 3.77 (s, 3H);

[0181] 13 C NMR (101 MHz, CDCl3) δ 202.4, 169.2, 133.8, 133.5, 130.7, 129.3, 52.7, 51.9, 47.3;

[0182] IR (KBr): 3317, 3040, 2952, 2854, 1743, 1529, 1440, 1356, 1220, 1136, 1093, 1014, 980, 812, 758, 697, 500 cm -1 ;

[0183] HRMS (APCI, m / z): [M + H] + Calcd. for C 11 H 12 ClNO2S + H, 258.0350; found, 258.0353.

[0184] Based on the above data, the structure of the obtained product is inferred:

[0185]

[0186] Example 19

[0187] This example provides a thioamide derivative and its preparation method.

[0188] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.8 mmol of sodium sulfide, 0.2 mmol of L-proline benzyl ester hydrochloride, 2 mL of dimethyl sulfoxide, and 0.4 mmol of 4-chlorophenyl gem-difluoroolefin are added to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, the stirring is stopped, the reaction is quenched by adding saturated sodium chloride aqueous solution, the reaction solution is extracted with ethyl acetate, the ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography to obtain the target product. The eluent used for column chromatography is petroleum ether and ethyl acetate with a volume ratio of 5:1; the yield of the product is 72%.

[0189] The structural characterization data of the product obtained in this example are as follows:

[0190] 1 H NMR(400MHz,CDCl3)δ7.38 - 7.36(m,5H),7.25(q,J=8.6Hz,4H),5.20(s,2H),5.09(dd,J=8.7,2.8Hz,1H),4.27 - 4.12(m,2H),3.71 - 3.56(m,2H),2.33 - 2.20(m,1H),2.16 - 1.96(m,3H);

[0191] 13 C NMR(101MHz,CDCl3)δ198.8,170.2,135.5,133.9,132.7,129.9,128.9,128.6,128.4,128.3,67.1,65.8,51.5,50.2,29.4,25.2;

[0192] IR(KBr):3037,2965,2882,1741,1485,1342,1267,1162,1095,1004,807,743,610,488cm -1 ;

[0193] HRMS(APCI,m / z):[M+H] + Calcd.for C 20 H 20 ClNO2S+H,374.0976;found,374.0980.

[0194] Deduce the structure of the product based on the above data:

[0195]

[0196] Example 20

[0197] This example provides a thioamide derivative and a preparation method thereof.

[0198] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.8 mmol of sodium sulfide, 0.2 mmol of methyl 2-(2-aminoacetamido)acetate hydrochloride, 2 mL of dimethyl sulfoxide, and 0.4 mmol of 4-chlorophenyl gem-difluoroolefin are added to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, the stirring is stopped, and the reaction is quenched by adding a saturated sodium chloride aqueous solution. The reaction solution is extracted with ethyl acetate, the ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography. The column chromatography eluent used is petroleum ether and ethyl acetate with a volume ratio of 1:1; the yield of the product is 63%.

[0199] The structure characterization data of the product obtained in this example are as follows:

[0200] 1 H NMR(400MHz,DMSO-d6)δ10.42(t,J=5.5Hz,1H),8.55(t,J=5.9Hz,1H),7.42-7.32(m,4H),4.30(d,J=5.4Hz,2H),3.99(s,2H),3.91(d,J=5.8Hz,2H),3.64(s,3H);

[0201] 13 C NMR(101MHz,DMSO-d6)δ202.5,170.6,168.1,137.0,131.8,131.2,128.5,52.2,50.5,48.3,41.0;

[0202] IR(KBr):3049,2991,2929,2856,1742,1673,1549,1445,1383,1267,1093,1030,903,755,701,596,556cm -1 ;

[0203] HRMS(APCI,m / z):[M+H] + Calcd.for C 13 H 15 ClN2O3S+H,315.0565;found,315.0565.

[0204] Based on the above data, the structure of the obtained product is deduced:

[0205]

[0206] Example 21

[0207] This example provides a thioamide derivative and a preparation method thereof.

[0208] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.8 mmol of sodium sulfide, 0.2 mmol of (S)-2-amino-4-(methylthio)butyramide hydrochloride, 2 mL of dimethyl sulfoxide, and 0.4 mmol of 4-chlorophenyl gem-difluoroolefin are added to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, the stirring is stopped, the reaction is quenched by adding a saturated sodium chloride aqueous solution, the reaction solution is extracted with ethyl acetate, the ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography to obtain the target product. The eluent used for column chromatography is petroleum ether and ethyl acetate with a volume ratio of 1:1; the yield of the product is 51%.

[0209] The structure characterization data of the product obtained in this example are as follows:

[0210] 1 H NMR(400MHz,CDCl3)δ8.53(d,J=7.6Hz,1H),7.34-7.22(m,4H),6.49(s,1H),6.14(s,1H),5.23(q,J=6.8Hz,1H),4.10-3.96(m,2H),2.51(qt,J=13.6,7.0Hz,2H),2.13(q,J=6.9Hz,2H),2.07(s,3H);

[0211] 13 C NMR(101MHz,CDCl3)δ202.5,172.6,134.1,133.5,130.5,129.1,57.5,52.0,30.1,29.9,15.4;

[0212] IR(KBr):3185,3029,2922,2857,1678,1496,1410,1270,1130,1092,1018,810,754,511cm -1 ;

[0213] HRMS(APCI,m / z):[M+H] + Calcd.for C 13 H 17 ClN2OS2+H,317.0544;found,317.0545.

[0214] Deduce the structure of the product based on the above data:

[0215]

[0216] Example 22

[0217] This example provides a thioamide derivative and a preparation method thereof.

[0218] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.8 mmol of sodium sulfide, 0.2 mmol of (3S,4R)-3-((benzo[d][1,3]dioxol-5-yloxy)methyl)-4-(4-fluorophenyl)piperidine hydrochloride, 2 mL of dimethyl sulfoxide, and 0.3 mmol of 4-chlorophenyl difluoromethylenecarboxylate are added to a 25-mL graduated tube. The reaction system is stirred at 25 °C for 10 minutes, then the stirring is stopped, and the reaction is quenched by adding saturated sodium chloride aqueous solution. The reaction solution is extracted with ethyl acetate, and the ethyl acetate layer is dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it is separated and purified by column chromatography to obtain the target product. The eluent used for column chromatography is petroleum ether and ethyl acetate with a volume ratio of 6:1; the yield of the product is 94%.

[0219] The structure characterization data of the product obtained in this example are as follows:

[0220] 1 H NMR(400MHz,CDCl3)δ7.43-7.29(m,4H),7.08-6.94(m,4H),6.64(dd,J=8.5,2.1Hz,1H),6.35(dd,J=34.6,2.5Hz,1H),6.13(ddd,J=36.8,8.5,2.5Hz,1H),5.97-5.92(m,0.43H),5.89(d,J=6.8Hz,2H),5.84-5.78(m,0.57H),4.61-4.16(m,3H),3.73-3.35(m,2H),3.28-2.69(m,3H),2.15-1.94(m,1H),1.88-1.76(m,1H),1.72-1.63(m,0.6H),1.41-1.34(m,0.4H);

[0221] 1313C NMR (101 MHz, CDCl3) δ 198.8, 198.7, 163.0, 162.9, 160.6, 160.5, 154.1, 153.7, 148.3, 148.2, 142.0, 141.9, 137.8, 137.8, 134.7, 134.6, 132.9, 132.9, 129.5, 129.4, 129.0, 129.0, 128.9, 128.8, 128.7, 128.6, 115.9, 115.8, 115.7, 115.6, 108.0, 107.9, 105.8, 105.3, 101.3, 101.2, 98.2, 97.7, 68.3, 68.2, 53.5, 51.1, 51.0, 50.2, 50.2, 43.6, 42.9, 42.8, 41.8, 34.0, 33.0;

[0222] IR (KBr): 3039, 2920, 2777, 1894, 1734, 1610, 1494, 1384, 1275, 1230, 1187, 1089, 1034, 938, 828, 738, 616, 541, 491 cm -1 ;

[0223] HRMS (APCI, m / z): [M+H] + Calcd. for C 27 H 25 ClNO3SF + H, 498.1301; found, 498.1307.

[0224] Based on the above data, the structure of the obtained product is deduced:

[0225]

[0226] Example 23

[0227] This example provides a thioamide derivative and a preparation method thereof.

[0228] The preparation method of the thioamide derivative is as follows: Under an air atmosphere, 0.6 mmol of sodium sulfide, 0.2 mmol of 8-chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 2 mL of dimethyl sulfoxide, and 0.3 mmol of 4-chlorophenyl gem-difluoroolefin were added to a 25-mL graduated tube. The reaction system was stirred at 25 °C for 10 minutes, the stirring was stopped, the reaction was quenched by adding a saturated sodium chloride aqueous solution, the reaction solution was extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and then rotary evaporated under reduced pressure to remove the solvent. Then, it was separated and purified by column chromatography to obtain the target product. The eluent used for column chromatography was petroleum ether and ethyl acetate with a volume ratio of 2:1; the yield of the product was 99%.

[0229] The structural characterization data of the product obtained in this example are as follows:

[0230] 1 H NMR(400MHz,CDCl3)δ8.35(dd,J=20.1,4.7Hz,1H),7.42(dd,J=8.3,4.3Hz,1H),7.25(d,J=1.2Hz,4H),7.18-6.99(m,4H),4.87-4.53(m,1H),4.29(s,2H),3.91-3.74(m,2H),3.49-3.22(m,3H),2.89-2.50(m,3H),2.46-2.07(m,3H);

[0231] 13 C NMR(101MHz,CDCl3)δ198.5,198.5,156.4,156.2,146.7,146.6,139.6,139.6,137.9,137.8,137.4,137.2,135.4,135.4,134.9,134.8,134.5,133.4,133.3,133.2,133.1,132.8,132.8,130.3,130.1,129.2,129.2,129.1,129.0,129.0,126.3,126.3,122.6,122.5,51.0,51.0,50.2,50.2,50.1,31.6,31.5,31.5,30.6,30.3,29.6,29.3;

[0232] IR(KBr):3039,2916,1735,1577,1489,1443,1363,1279,1246,1150,1095,989,883,830,735,492cm -1 ;

[0233] HRMS(APCI, m / z): [M+H] + Calcd. for C 27 H 24 Cl2N2S+H, 479.1110; found, 479.1116.

[0234] Based on the above data, infer the structure of the obtained product:

[0235]

[0236] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A method for synthesizing a thioamide derivative, characterized in that, It includes the following steps: mixing a gem-difluoroolefin, an amine compound, a sulfonium salt and an organic solvent I for reaction, and subjecting the obtained product to subsequent treatment to obtain a thioamide derivative; the molar ratio of the amine compound to the gem-difluoroolefin is 1:3 to 3:1, and the molar ratio of the amine compound to the sulfonium salt is 1:1 to 8; the gem-difluoroolefin is an aryl, substituted aryl, heteroaryl or substituted heteroaryl gem-difluoroolefin; the amine compound is a cyclic amine compound, a chain amine compound or an amino acid ester hydrochloride.

2. The synthesis method of the thioamide derivative according to claim 1, wherein The gem-difluoroolefin is one of phenyl gem-difluoroolefin, p-chlorophenyl gem-difluoroolefin, o-chlorophenyl gem-difluoroolefin, m-chlorophenyl gem-difluoroolefin, p-bromophenyl gem-difluoroolefin, p-fluorophenyl gem-difluoroolefin, m-nitrophenyl gem-difluoroolefin, p-methoxycarbonylphenyl gem-difluoroolefin, p-methylsulfonylphenyl gem-difluoroolefin, p-acetamidophenyl gem-difluoroolefin, p-phenylphenyl gem-difluoroolefin, p-trifluoromethylphenyl gem-difluoroolefin, p-morpholinophenyl gem-difluoroolefin, p-methoxyphenyl gem-difluoroolefin, 3,4,5-trichlorophenyl gem-difluoroolefin, p-methylthiophenyl gem-difluoroolefin, p-tert-butylphenyl gem-difluoroolefin, m-cyanophenyl gem-difluoroolefin, o-methylphenyl gem-difluoroolefin, m-methylphenyl gem-difluoroolefin, p-methylphenyl gem-difluoroolefin, 3,4-dimethoxyphenyl gem-difluoroolefin, 2-naphthyl gem-difluoroolefin, 1-naphthyl gem-difluoroolefin, 2-quinolyl gem-difluoroolefin, 2-benzothienyl gem-difluoroolefin, 3-pyridyl, 3-indolyl gem-difluoroolefin, 5-(2-dimethylaminopyrimidine) gem-difluoroolefin, 4-(prop-2-yn-1-yloxy)phenyl gem-difluoroolefin, 2-(6,11-dihydro-11-oxodibenzo[b,e]oxepin) gem-difluoroolefin, 1,1-difluoro-2,2-distyrene.

3. The method for synthesizing the thioamide derivative according to claim 1, wherein When the amine compound is a cyclic amine compound, the cyclic amine compound is one of pyrrolidine, piperidine, cyclohexylimine, tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, morpholine, thiomorpholine, N-phenylpiperazine, 8-chloro-11-(piperidin-4-ylidene)-6-11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, (3S,4R)-3-((benzo[d][1,3]dioxol-5-yloxymethyl)-4-(4-fluorophenyl)piperidine. Or, when the amine compound is a chain amine compound, the chain amine compound is one of diethylamine, di-n-butylamine, dibenzylamine, aniline, n-butylamine, 2-methoxyethylamine, benzylamine, N-methylcyclopropylamine, N-methylallylamine, N-methylbenzylamine, N-methylaniline, N-methyl-γ-[4-(trifluoromethyl)phenoxy]amphetamine, phenylmethyl N-[(1S)-5-amino-1-[(phenylamino)carbonyl]pentyl]carbamate. Or, when the amine compound is an amino acid ester hydrochloride, the amino acid ester hydrochloride is one of methyl glycinate hydrochloride, benzyl L-prolinate hydrochloride, benzyl L-leucinate hydrochloride, tert-butyl L-isoleucinate hydrochloride, benzyl L-alaninate hydrochloride, tert-butyl L-methioninate hydrochloride, tert-butyl L-phenylalaninate hydrochloride, methyl L-tryptophanate hydrochloride, tert-butyl L-valinate hydrochloride, tert-butyl L-threoninate hydrochloride, tert-butyl L-tyrosinate hydrochloride, methyl 2-(2-aminoacetamido)acetate hydrochloride, (S)-2-amino-4-(methylthio)butanamide hydrochloride.

4. The synthesis method of the thioamide derivative according to claim 1, wherein The organic solvent I is at least one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, N-methylpyrrolidone, 1,4-dioxane.

5. The synthesis method of the thioamide derivative according to claim 1, characterized in that, The sulfur salt is at least one of potassium sulfide, sodium sulfide, lithium sulfide.

6. The synthesis method of the thioamide derivative according to claim 1, wherein The reaction temperature is 25-120 °C, and the reaction time is 10 min-24 h; the reaction is carried out in an air, nitrogen or argon atmosphere.

7. The synthesis method of the thioamide derivative according to claim 1, characterized in that, The subsequent treatment refers to quenching the reaction, extracting the reaction solution with an organic solvent II, separating the aqueous layer, then drying the organic layer with a desiccant, filtering and rotary evaporating under reduced pressure to remove the organic solvent II to obtain a crude product, and purifying by column chromatography to obtain the thioamide derivative.

8. A thioamide derivative, characterized in that, Prepared by the synthesis method according to any one of claims 1 to 7.

9. The thioamide derivative according to claim 8, wherein The structure of the thioamide derivative is as follows: Among them, R 1 is one of phenyl, p-chlorophenyl, o-chlorophenyl, m-chlorophenyl, p-bromophenyl, p-fluorophenyl, m-nitrophenyl, p-methyl formate phenyl, p-methylsulfonyl phenyl, p-acetamido phenyl, p-phenyl phenyl, p-trifluoromethyl phenyl, p-morpholine phenyl, p-methoxy phenyl, 3,4,5-trichlorophenyl, p-methylthio phenyl, p-tert-butyl phenyl, m-cyano phenyl, o-methyl phenyl, m-methyl phenyl, p-methyl phenyl, 3,4-dimethoxy phenyl, 2-naphthyl, 1-naphthyl, 2-quinolyl, 2-benzothienyl, 3-pyridyl, 3-indolyl, 5-(2-dimethylaminopyrimidine) group, 4-(prop-2-yn-1-yloxy) phenyl, 2-(6,11-dihydro-11-oxodibenzo[b,e]oxepin) group; The R 2 is one of hydrogen or phenyl; R 3 / R 4 is one of ethyl / ethyl, n-butyl / n-butyl, benzyl / benzyl, hydrogen / phenyl, hydrogen / n-butyl, hydrogen / 2-methoxyethyl, hydrogen / benzyl, methyl / cyclopropyl, methyl / allyl, methyl / benzyl, methyl / γ-[4-(trifluoromethyl)phenoxy]phenylpropyl, hydrogen / phenylmethyl N-[(1S)-5-amino-1-[(phenylamino)carbonyl]pentyl]carbamate 10. Use of a thioamide derivative according to any one of claims 8 or 9 in the medical field.

Images