A thiocarbamic acid derivative, a preparation method and application thereof

Abstract

The application discloses a thiocarbamic acid ester derivative, a preparation method and application thereof, and belongs to the field of medicinal chemistry. The thiocarbamic acid ester derivative has excellent broad-spectrum antifungal effect and has the advantages of simple synthesis method, and has important reference significance for developing a novel high-efficiency antiphysiological pathogenic fungus agent.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a thiocarbamate derivative, its preparation method, and its application. Background Technology

[0002] Peanut (Arachis hypogaea L.) is a globally important oilseed and food crop, with China having the world's largest peanut planting area. Despite its immense economic and nutritional value, peanut cultivation is severely hampered by various plant pathogens. Among these, peanut stem rot, caused by the soil-borne fungus *Sclerotium rolfsii*, can infect peanuts at all growth stages, leading to severe wilting and pod rot. In severe cases, this disease can cause up to 50% of global yield loss and is currently considered one of the most destructive soil-borne peanut diseases in China. Due to the lack of resistant varieties, the control of peanut stem rot mainly relies on chemical fungicides, applied through seed treatment, foliar spraying, or soil irrigation. Although traditional commercial fungicides such as thifluzamide and certain triazole agents are widely used, their long-term and excessive use has led to serious challenges such as declining field efficacy and increasingly prominent environmental problems. Therefore, there is an urgent need to develop novel, highly efficient, and environmentally friendly fungicides with unique mechanisms of action for the sustainable management of this disease.

[0003] Thiocarbamates are primarily used as herbicides and insecticides, but their potential as agricultural fungicides remains largely untapped. The sulfur atom in their structural framework can disrupt microbial metabolic processes by donating electrons to chelate essential metal ions, thereby endowing them with potent biological activity. Furthermore, the -NH-C(=S)SH group can form hydrogen bonds with the bioactive site. Therefore, this multifunctional pharmacophore has attracted widespread attention in medicinal chemistry, and recent studies have reported on the antibacterial applications of related derivatives. However, the rational design and application of thiocarbamate groups in agricultural antifungal agents still require further exploration.

[0004] Laccase is a multi-copper oxidase. Fungal laccases possess highly conserved copper-binding regions and exhibit extremely low homology (<25%) with homologous proteins from other species, making them a highly specific and attractive antifungal target. Although PMDD is currently the only registered fungicide targeting laccase, recent studies have revealed the potent laccase-inhibiting potential of dithiocarbamate derivatives. Based on our previous findings that thiourea core compounds possess broad-spectrum antifungal and laccase-inhibiting activities, and recognizing the bioisosteric similarity between thiourea and thiocarbamates, we rationally designed and synthesized a series of novel thiocarbamate derivatives to further explore their biological potential as novel fungicidal candidates. Through in vitro enzyme activity assays, ultrastructural observations (SEM and TEM), molecular docking, and transcriptomics analysis, we systematically elucidated their mechanism of action. Summary of the Invention

[0005] The purpose of this invention is to provide a thiocarbamate derivative, its preparation method, and its application, to solve the problems existing in the prior art. The thiocarbamate derivative of this invention exhibits highly efficient antifungal activity, demonstrating excellent broad-spectrum antifungal effects, and has the advantage of a simple synthesis method. It has important reference value for the development of novel and highly efficient antifungal agents against plant pathogenic fungi.

[0006] To achieve the above objectives, the present invention provides the following solution:

[0007] The thiocarbamate derivatives of this invention have the following general structural formula I:

[0008] ;

[0009] Among them, R 1 It is one or more of halogen, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy; the substituent used for substitution is halogen; R 1 It can be a single substitution or a multiple substitution, and the substitution position includes one or more of the following: ortho, meta, and para.

[0010] R 2 For methyl, R 3 H or methyl, X is an O or S atom.

[0011] The present invention discloses a method for preparing thiocarbamate derivatives, which uses substituted phenol or substituted thiophenol 1 and compound 2 as reaction substrates, and reacts them in a solvent system containing an alkali to prepare the target product, thiocarbamate derivatives.

[0012] The alkali is sodium hydride or sodium bicarbonate.

[0013] The solvent is N,N-dimethylformamide or anhydrous ethanol.

[0014] Furthermore, the molar ratio of compound 2, substituted phenol or substituted thiophenol, and base is 1:1.2:1.

[0015] The reaction route is shown below:

[0016] .

[0017] Depending on the substrate—compound 2—the reaction can proceed via either route one or route two:

[0018] The steps of Route 1 include:

[0019] Dimethylaminothioformyl chloride (1.0 equivalent), substituted phenol or substituted thiophenol (1.2 equivalent), and sodium hydride (1.0 equivalent) were added to a dry reaction flask. Using N,N-dimethylformamide (10 mL) as solvent, the reaction was carried out at 80 °C for 1 h, and the reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, the residue was dissolved in 20 mL of saturated ammonium chloride solution, then extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography (dichloromethane / petroleum ether = 1:2, V / V) to obtain the target product.

[0020] Preferably, the substituted phenol is selected from one of o-fluorophenol, m-fluorophenol, p-fluorophenol, o-chlorophenol, m-chlorophenol, p-chlorophenol, o-bromophenol, m-bromophenol, p-bromophenol, o-trifluoromethylphenol, m-trifluoromethylphenol, p-trifluoromethylphenol, o-methoxyphenol, m-methoxyphenol, and p-methoxyphenol.

[0021] Preferably, the substituted thiophenol is selected from one of o-fluorothiophenol, m-fluorothiophenol, p-fluorothiophenol, o-chlorothiophenol, m-chlorothiophenol, p-chlorothiophenol, o-bromothiophenol, m-bromothiophenol, p-bromothiophenol, o-trifluoromethylthiophenol, m-trifluoromethylthiophenol, p-trifluoromethylthiophenol, o-methylthiophenol, m-methylthiophenol, p-methylthiophenol, o-methoxythiophenol, m-methoxythiophenol, p-methoxythiophenol, 3,5-difluorothiophenol, 3,4-difluorothiophenol, 2,4-dichlorothiophenol, 3,5-dichlorothiophenol, 3,4-dichlorothiophenol, and 3,5-bistrifluoromethylthiophenol.

[0022] The steps of Route 2 include:

[0023] Methyl isothiocyanate (1.0 equivalent), substituted phenol or substituted thiophenol (1.2 equivalent), and sodium bicarbonate (1.0 equivalent) were added to a dry reaction flask. Anhydrous ethanol (10 mL) was used as the solvent, and the reaction was carried out at room temperature for 1 h. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was complete, the residue was dissolved in 20 mL of saturated ammonium chloride solution, then extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography (dichloromethane / petroleum ether = 1:2, V / V) to obtain the target product.

[0024] As a preferred embodiment of the present invention, the substituted thiophenol is selected from one of p-fluorothiophenol, p-chlorothiophenol, p-bromothiophenol, and p-trifluoromethylthiophenol.

[0025] The present invention also provides the use of the above-mentioned thiocarbamate derivatives in the preparation of antifungal drugs.

[0026] The fungi include one or more of the following: apple rot fungus, sclerotium rot fungus, gray mold fungus, rhizoctonia solani fungus, Alternaria alternata, wheat scab, Pythium graminearum, Curvularia crescentis, Phytophthora capsici, and Sclerotium sclerotiorum.

[0027] The present invention also provides an antifungal drug, wherein the thiocarbamate derivative is the active pharmaceutical ingredient; the fungi include one or more of the following: apple rot fungus, sclerotium rot fungus, gray mold fungus, rhizoctonia solani fungus, Alternaria alternata, wheat scab, Pythium graminearum, Curvularia crescentis, Phytophthora capsici, and Sclerotium sclerotiorum.

[0028] The beneficial effects of this invention are reflected in:

[0029] This invention provides a thiocarbamate derivative that exhibits excellent broad-spectrum antifungal effects. The invention offers the advantage of a simple synthetic method and provides important reference for the development of novel and highly effective antifungal agents against plant pathogenic fungi. Detailed Implementation

[0030] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be construed as limiting the invention, but rather as a more specific description of certain aspects, features, and embodiments of the invention.

[0031] It should be understood that the terminology used in this invention is for describing specific embodiments only and is not intended to limit the invention. Furthermore, for numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included within the invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0032] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0033] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0034] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0035] The column chromatography conditions in this embodiment of the invention are: 200-300 mesh silica gel powder. The molar numbers indicated in this embodiment refer to the amount of the substance used in the reaction system.

[0036] Example 1: Preparation of compounds a1-a15

[0037]

[0038] General synthetic method: Dimethylaminothioformyl chloride (1.0 mmol, 1.0 equivalent), the corresponding substituted phenol (1.2 mmol, 1.2 equivalent), and sodium hydride (1.0 mmol, 1.0 equivalent) were added to a dry reaction flask, using N,N-dimethylformamide (10 mL) as solvent. The reaction was carried out at 80 °C for 1 h, and the reaction progress was monitored by TLC. After the reaction was completed, the residue was dissolved in 20 mL of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography (dichloromethane / petroleum ether = 1:2) to obtain the target compound.

[0039] Taking compound a1 as an example: dimethylcarbamoyl chloride (1.0 mmol), o-fluorophenol (1.2 mmol), and sodium hydride (1.0 mmol) were dissolved in N,N-dimethylformamide (10 mL), and reacted at 80 °C for 1 h. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried, concentrated under reduced pressure, and purified by thin-layer chromatography (dichloromethane / petroleum ether = 1:2) to obtain the target compound O-(2-fluorophenyl)dimethylaminothiocarbamate (a1).

[0040]

[0041] Yellow solid, yield: 90%; mp: 68-67 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.27 – 7.20 (m, 1H), 7.19 – 7.10 (m, 3H), 3.46 (s, 3H), 3.37 (s, 3H). 13 CNMR (101 MHz, Chloroform-d) δ 186.91, 154.50 (d, J = 248.7 Hz), 141.36 (d, J= 12.0 Hz), 127.18 (d, J = 7.1 Hz), 125.05, 124.25 (d, J = 3.9 Hz), 116.61(d, J = 18.4 Hz), 43.57, 38.84. 19 F NMR (377 MHz, Chloroform-d) δ -128.56.HRMS (ESI) calculated for C9H 10 FNOS [M + H] + , 200.0540; found, 200.0553.

[0042] The preparation of compound a1 differed from that of compound a1 in Example 1 only in that o-fluorophenol was replaced with m-fluorophenol. Compound a2 was obtained: O-(3-fluorophenyl)dimethylaminothiocarbamate.

[0043]

[0044] Light yellow liquid, yield: 85%; 1H NMR (400 MHz, Chloroform-d) δ7.39 – 7.29 (m, 1H), 7.00 – 6.93 (m, 1H), 6.90 – 6.80 (m, 2H), 3.45 (s, 3H), 3.33 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 187.17, 162.74 (d, J = 247.3Hz), 154.79 (d, J = 11.2 Hz), 129.82 (d, J = 9.4 Hz), 118.80 (d, J = 3.4 Hz), 112.93 (d, J = 21.0 Hz), 111.04 (d, J = 24.0 Hz), 43.32, 38.80. 19 F NMR (377MHz, Chloroform-d) δ -111.42. HRMS (ESI) calculated for C9H 10 FNOS [M + H] + ,200.0540; found, 200.0530.

[0045] The preparation of compound a1 differed from that of compound a1 in Example 1 only in that o-fluorophenol was replaced with p-fluorophenol. Compound a3 was obtained: O-(4-fluorophenyl)dimethylaminothiocarbamate.

[0046]

[0047] Yellow solid, yield: 90%; mp: 51-52 ℃; 1 H NMR (400 MHz, Chloroform-d) δ 7.30 (d, J = 9.1 Hz, 1H), 7.28 – 7.22 (m, 3H), 3.67 (s, 3H), 3.56 (s,3H). 13 C NMR (101 MHz, Chloroform-d) δ 187.74, 160.29 (d, J = 244.2 Hz), 149.93 (d, J = 2.9 Hz), 124.25 (d, J = 8.6 Hz), 115.79 (d, J = 23.5 Hz), 43.33, 38.73. 19F NMR (377 MHz, Chloroform-d) δ -116.87. HRMS (ESI) calculated for C9H 10 FNOS [M + H] + , 200.0540; found, 200.0527.

[0048] The only difference from the preparation of compound a1 in Example 1 is that o-fluorophenol was replaced with o-chlorophenol. Compound a4 was obtained: O-(2-chlorophenyl)dimethylaminothiocarbamate.

[0049]

[0050] Light yellow liquid, yield: 75%; 1 H NMR (400 MHz, Chloroform-d) δ7.47 – 7.40 (m, 1H), 7.35 – 7.26 (m, 1H), 7.23 – 7.13 (m, 2H), 3.46 (s, 3H), 3.38 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 186.49, 149.97, 130.19,127.61, 127.47, 127.02, 125.21, 43.47, 38.85. HRMS (ESI) calculated forC9H 10 ClNOS [M + H] + , 216.0244; found, 216.0235.

[0051] The only difference from the preparation of compound a1 in Example 1 is that o-fluorophenol was replaced with m-chlorophenol. Compound a5 was obtained: O-(3-chlorophenyl)dimethylaminothiocarbamate.

[0052]

[0053] Light yellow liquid, yield: 76%; 1H NMR (400 MHz, Chloroform-d) δ7.35 – 7.27 (m, 1H), 7.25 – 7.21 (m, 1H), 7.09 (t, J = 2.1 Hz, 1H), 7.01 –6.94 (m, 1H), 3.44 (s, 3H), 3.33 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ187.16, 154.42, 134.34, 129.84, 126.16, 123.54, 121.41, 43.35, 38.83. HRMS(ESI) calculated for C9H 10 ClNOS [M + H] + , 216.0244; found, 216.0240.

[0054] The preparation of compound a1 differed from that in Example 1 only in that o-fluorophenol was replaced with p-chlorophenol. Compound a6 was obtained: O-(4-chlorophenyl)dimethylaminothiocarbamate.

[0055]

[0056] Yellow solid, yield: 75%; mp: 52-53 ℃; 1 H NMR (400 MHz, Chloroform-d) δ 7.37 – 7.31 (m, 2H), 7.03 – 6.97 (m, 2H), 3.44 (s, 3H), 3.33 (s, 3H). 13 CNMR (101 MHz, Chloroform-d) δ 187.40, 152.50, 131.30, 129.24, 124.26, 43.35,38.80. HRMS (ESI) calculated for C9H 10 ClNOS [M + H] + , 216.0244; found,216.0245.

[0057] The only difference from the preparation of compound a1 in Example 1 is that o-fluorophenol was replaced with o-bromophenol. Compound a7 was obtained: O-(2-bromophenyl)dimethylaminothiocarbamate.

[0058]

[0059] Transparent liquid, yield: 70%; 1 H NMR (400 MHz, Chloroform-d) δ 7.64– 7.56 (m, 1H), 7.39 – 7.31 (m, 1H), 7.18 – 7.11 (m, 2H), 3.47 (s, 3H), 3.39(s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 186.33, 151.14, 133.20, 128.18,127.31, 125.32, 117.12, 43.48, 38.93. HRMS (ESI) calculated for C9H 10 BrNOS [M+ H] + , 259.9739; found, 259.9720.

[0060] The only difference from the preparation of compound a1 in Example 1 is that o-fluorophenol was replaced with m-bromophenol. Compound a8 was obtained: O-(3-bromophenyl)dimethylaminothiocarbamate.

[0061]

[0062] White solid, yield: 80%; mp: 74-75 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.42 – 7.35 (m, 1H), 7.29 – 7.22 (m, 2H), 7.06 – 6.99 (m, 1H), 3.45 (s,3H), 3.33 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 187.23, 154.39, 130.11,129.08, 126.35, 122.07, 121.85, 43.35, 38.80. HRMS (ESI) calculated forC9H 10 BrNOS [M + H] + , 259.9739; found, 259.9718.

[0063] The only difference from the preparation of compound a1 in Example 1 is that o-fluorophenol was replaced with p-bromophenol. Compound a9 was obtained: O-(4-bromophenyl)dimethylaminothiocarbamate.

[0064]

[0065] White solid, yield: 80%; mp: 78-79 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.53 – 7.47 (m, 2H), 6.98 – 6.92 (m, 2H), 3.44 (s, 3H), 3.33 (s, 3H). 13 CNMR (101 MHz, Chloroform-d) δ 187.30, 153.05, 132.22, 124.71, 119.09, 43.36,38.83. HRMS (ESI) calculated for C9H 10 BrNOS [M + H] + , 259.9739; found,259.9735.

[0066] The only difference from the preparation of compound a1 in Example 1 is that o-fluorophenol is replaced with o-trifluoromethylphenol. Compound a10 is obtained: O-(2-trifluoromethylphenyl)dimethylaminothiocarbamate.

[0067]

[0068] Transparent liquid, yield: 70%; 1 H NMR (400 MHz, Chloroform-d) δ 7.66(d, J = 8.0 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.30(d, J = 8.2 Hz, 1H), 3.46 (s, 3H), 3.36 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 186.61, 150.96, 132.38, 126.64 (q, J = 4.9 Hz), 126.31, 125.91, 123.10 (q, J = 31.3 Hz), 123.05 (q, J = 272.8 Hz), 43.42, 38.73. 19 F NMR (377 MHz,Chloroform-d) δ -61.26. HRMS (ESI) calculated for C 10 H 10 F3NOS [M + H] + ,250.0508; found, 250.0493.

[0069] The only difference from the preparation of compound a1 in Example 1 is that o-fluorophenol is replaced with m-trifluoromethylphenol. Compound a11 is obtained: O-(3-trifluoromethylphenyl)dimethylaminothiocarbamate.

[0070]

[0071] Light yellow liquid, yield: 75%; 1 H NMR (400 MHz, Chloroform-d) δ7.51 (d, J = 5.4 Hz, 2H), 7.34 (s, 1H), 7.31 – 7.25 (m, 1H), 3.46 (s, 3H), 3.36 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 187.08, 154.00, 131.58 (q, J =32.9 Hz), 129.66, 126.64, 123.64 (q, J = 272.4 Hz), 122.64 (q, J = 3.8 Hz),120.19 (q, J = 3.9 Hz), 43.35, 38.80. 19 F NMR (377 MHz, Chloroform-d) δ -62.55. HRMS (ESI) calculated for C 10 H 10 F3NOS [M + H] + , 250.0508; found,250.0505.

[0072] The only difference from the preparation of compound a1 in Example 1 is that o-fluorophenol was replaced with p-trifluoromethylphenol. Compound a12 was obtained: O-(4-trifluoromethylphenyl)dimethylaminothiocarbamate.

[0073]

[0074] White solid, yield: 70%; mp: 104-105 ℃; 1 H NMR (400 MHz, Chloroform-d) δ 7.67 (d, J = 0.7 Hz, 1H), 7.64 (d, J = 0.7 Hz, 1H), 7.20 (d, J = 0.8 Hz,1H), 7.18 (d, J = 0.9 Hz, 1H), 3.46 (s, 3H), 3.36 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 186.90, 156.38, 128.06 (q, J = 32.8 Hz), 126.52 (q, J = 3.8Hz), 123.96 (q, J = 272.0 Hz), 123.41, 43.33, 38.84. 19 F NMR (377 MHz,Chloroform-d) δ -62.14. HRMS (ESI) calculated for C 10 H 10 F3NOS [M + H] + ,250.0508; found, 250.0518.

[0075] The only difference from the preparation of compound a1 in Example 1 is that o-fluorophenol is replaced with o-methoxyphenol. Compound a13 is obtained: O-(2-methoxyphenyl)dimethylaminothiocarbamate.

[0076]

[0077] Light yellow liquid, yield: 70%; 1H NMR (400 MHz, Chloroform-d) δ 7.25– 7.19 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.01 – 6.92 (m, 2H), 3.83 (s, 3H), 3.46 (s, 3H), 3.36 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 187.98, 151.63,143.00, 126.89, 124.07, 120.58, 112.68, 56.00, 43.38, 38.73. HRMS (ESI)calculated for C 10 H 13 NO2S [M + H] + , 212.0740; found, 212.0751.

[0078] The only difference from the preparation of compound a1 in Example 1 is that o-fluorophenol was replaced with m-methoxyphenol. Compound a14 was obtained: O-(3-methoxyphenyl)dimethylaminothiocarbamate.

[0079]

[0080] Yellow liquid, yield: 65%; 1 H NMR (400 MHz, Chloroform-d) δ 7.31 –7.25 (m, 1H), 6.83 – 6.78 (m, 1H), 6.71 – 6.63 (m, 1H), 6.63 (t, J = 2.3 Hz,1H), 3.80 (s, 3H), 3.45 (s, 3H), 3.33 (s, 3H). 13 C NMR (101 MHz, Chloroform-d)δ 187.62, 160.32, 154.99, 129.46, 115.04, 111.73, 108.87, 55.44, 43.25,38.74. HRMS (ESI) calculated for C 10 H 13 NO2S [M + H] + , 212.0740; found,212.0744.

[0081] The only difference from the preparation of compound a1 in Example 1 is that o-fluorophenol was replaced with p-methoxyphenol. Compound a15 was obtained: O-(4-methoxyphenyl)dimethylaminothiocarbamate.

[0082]

[0083] Light yellow solid, yield: 70%; mp: 64-65 ℃; 1 H NMR (400 MHz, Chloroform-d) δ 7.28 – 7.22 (m, 2H), 7.20 – 7.14 (m, 2H), 4.08 (s, 3H), 3.72 (s, 3H), 3.60 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 188.34, 157.30,147.69, 123.49, 114.16, 55.55, 43.30, 38.67. HRMS (ESI) calculated forC 10 H 13 NO2S [M + H] + , 212.0740; found, 212.0750.

[0084] Example 2: Preparation of compounds b1-b24

[0085] General synthetic method: Dimethylaminothioformyl chloride (1.0 mmol, 1.0 equivalent), the corresponding substituted thiophenol (1.2 mmol, 1.2 equivalent), and sodium hydride (1.0 mmol, 1.0 equivalent) were added to a dry reaction flask, using N,N-dimethylformamide (10 mL) as solvent. The reaction was carried out at 80 °C for 1 h, and the reaction progress was monitored by TLC. After the reaction was completed, the residue was dissolved in 20 mL of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography (dichloromethane / petroleum ether = 1:2) to obtain the target compound.

[0086] Taking compound b1 as an example: dimethylcarbamoyl chloride (1.0 mmol), o-fluorothiophenol (1.2 mmol), and sodium hydride (1.0 mmol) were dissolved in N,N-dimethylformamide (10 mL), and reacted at 80°C for 1 h. The post-treatment was the same as in Example 1.

[0087]

[0088] White solid, yield: 90%; mp: 150-151 ℃; 1 H NMR (400 MHz, Chloroform-d) δ 7.55 – 7.42 (m, 2H), 7.27 – 7.15 (m, 2H), 3.55 (s, 3H), 3.52 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 195.14, 163.20 (d, J = 249.9 Hz), 138.66, 132.97 (d, J = 8.3 Hz), 124.74 (d, J = 3.8 Hz), 119.30 (d, J = 17.6Hz), 116.33 (d, J = 22.8 Hz), 45.83, 42.17. 19 F NMR (377 MHz, Chloroform-d) δ-105.46. HRMS (ESI) calculated for C9H 10 FNS2 [M + H] + , 216.0311; found,216.0318.

[0089] The preparation of compound b1 differed from that in Example 2 only in that o-fluorothiophenol was replaced with m-fluorothiophenol. Compound b2 was obtained: 3-fluorophenyl dimethyl dithiocarbamate.

[0090]

[0091] White solid, yield: 90%; mp: 116-117 ℃; 1 H NMR (400 MHz, Chloroform-d) δ 7.44 – 7.37 (m, 1H), 7.28 – 7.14 (m, 3H), 3.55 (s, 3H), 3.49 (s, 3H). 13CNMR (101 MHz, Chloroform-d) δ 196.41, 162.46 (d, J = 248.9 Hz), 133.41 (d, J= 8.2 Hz), 132.75 (d, J = 3.2 Hz), 130.26 (d, J = 8.1 Hz), 123.92 (d, J =22.2 Hz), 117.26 (d, J = 21.0 Hz), 45.70, 42.07. 19 F NMR (377 MHz, Chloroform-d) δ -111.88. HRMS (ESI) calculated for C9H 10 FNS2 [M + H] + , 216.0311; found,216.0315.

[0092] The preparation of compound b1 differed from that of compound b1 in Example 2 only in that o-fluorothiophenol was replaced with p-fluorothiophenol. Compound b3 was obtained: 4-fluorophenyl dimethyl dithiocarbamate.

[0093]

[0094] White solid, yield: 90%; mp: 120-121 ℃; 1 H NMR (400 MHz, Chloroform-d) δ 7.49 – 7.37 (m, 2H), 7.18 – 7.08 (m, 2H), 3.55 (s, 3H), 3.49 (s, 3H). 13 CNMR (101 MHz, Chloroform-d) δ 197.44, 163.97 (d, J = 250.9 Hz), 139.12 (d, J= 8.8 Hz), 127.23 (d, J = 3.4 Hz), 116.40 (d, J = 22.1 Hz), 45.82, 41.96. 19 FNMR (377 MHz, Chloroform-d) δ -109.95. HRMS (ESI) calculated for C9H 10 FNS2 [M+ H] + , 216.0311; found, 216.0317.

[0095] The only difference from the preparation of compound b1 in Example 2 is that o-fluorothiophenol is replaced with o-chlorothiophenol. Compound b4 is obtained: 2-chlorophenyl dimethyl dithiocarbamate.

[0096]

[0097] White solid, yield: 90%; mp: 89-90 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.59 – 7.53 (m, 2H), 7.47 – 7.40 (m, 1H), 7.37 – 7.30 (m, 1H), 3.55 (s,3H), 3.52 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 194.98, 140.55, 139.23,131.79, 131.06, 130.32, 127.48, 45.64, 42.19. HRMS (ESI) calculated forC9H 10 ClNS2 [M + H] + , 232.0016; found, 232.0017.

[0098] The preparation of compound b1 differed from that in Example 2 only in that o-fluorothiophenol was replaced with m-chlorothiophenol. Compound b5 was obtained: 3-chlorophenyl dimethyl dithiocarbamate.

[0099]

[0100] White solid, yield: 85%; mp: 70-71 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.49 – 7.41 (m, 2H), 7.40 – 7.34 (m, 2H), 3.55 (s, 3H), 3.49 (s, 3H). 13 CNMR (101 MHz, Chloroform-d) δ 196.33, 136.70, 135.18, 134.41, 133.37, 130.23,130.08, 45.73, 42.08. HRMS (ESI) calculated for C9H 10 ClNS2 [M + H] +, 232.0016;found, 232.0026.

[0101] The only difference from the preparation of compound b1 in Example 2 is that o-fluorothiophenol was replaced with p-chlorothiophenol. Compound b6 was obtained: 4-chlorophenyl dimethyl dithiocarbamate.

[0102]

[0103] White solid, yield: 92%; mp: 93-94 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.44 – 7.35 (m, 4H), 3.55 (s, 3H), 3.48 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 196.74, 138.25, 136.56, 130.25, 129.42, 45.77, 42.04. HRMS(ESI) calculated for C9H 10 ClNS2 [M + H] + , 232.0016; found, 232.0023.

[0104] The only difference from the preparation of compound b1 in Example 2 is that o-fluorothiophenol was replaced with o-bromothiophenol. Compound b7 was obtained: 2-bromophenyl dimethyl dithiocarbamate.

[0105]

[0106] Light yellow solid, yield: 87%; mp: 72-73 ℃; 1 H NMR (400 MHz, Chloroform-d) δ 7.75 – 7.72 (m, 1H), 7.60 – 7.57 (m, 1H), 7.43 – 7.30 (m, 2H), 3.55 (s, 3H), 3.52 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 195.00,139.26, 133.63, 133.21, 131.89, 131.74, 128.17, 45.63, 42.19. HRMS (ESI)calculated for C9H 10 BrNS2 [M + H]+ , 275.9511; found, 275.9501.

[0107] The preparation of compound b1 differed from that in Example 2 only in that o-fluorothiophenol was replaced with m-bromothiophenol. Compound b8 was obtained: 3-bromophenyl dimethyl dithiocarbamate.

[0108]

[0109] White solid, yield: 89%; mp: 86-87 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.64 – 7.57 (m, 2H), 7.45 – 7.37 (m, 1H), 7.34 – 7.29 (m, 1H), 3.55 (s,3H), 3.48 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 196.30, 139.46, 135.65,133.63, 133.10, 130.38, 122.34, 45.76, 42.11. HRMS (ESI) calculated forC9H 10 BrNS2 [M + H] + , 275.9511; found, 275.9505.

[0110] The preparation of compound b1 differed from that in Example 2 only in that o-fluorothiophenol was replaced with p-bromothiophenol. Compound b9 was obtained: 4-bromophenyl dimethyl dithiocarbamate.

[0111]

[0112] White solid, yield: 92%; mp: 94-95 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.60 – 7.53 (m, 2H), 7.36 – 7.28 (m, 2H), 3.54 (s, 3H), 3.48 (s, 3H). 13 CNMR (101 MHz, Chloroform-d) δ 196.54, 138.47, 132.38, 130.84, 124.99, 45.78,42.08. HRMS (ESI) calculated for C9H10 BrNS2 [M + H] + , 275.9511; found,275.9496.

[0113] The only difference from the preparation of compound b1 in Example 2 is that o-fluorothiophenol was replaced with o-trifluoromethylthiophenol. Compound b10 was obtained: 2-trifluoromethylphenyl dimethyl dithiocarbamate.

[0114]

[0115] White solid, yield: 87%; mp: 64-65 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.82 – 7.77 (m, 1H), 7.67 – 7.55 (m, 3H), 3.53 (s, 3H), 3.52 (s, 3H). 13 CNMR (101 MHz, Chloroform-d) δ 195.88, 141.61, 133.96 (q, J = 29.9 Hz), 132.24, 130.41, 130.37, 126.93 (q, J = 5.5 Hz), 123.27 (q, J = 274.0 Hz),45.69, 42.22. 19 F NMR (377 MHz, Chloroform-d) δ -59.92. HRMS (ESI) calculated for C 10 H 10 F3NS2 [M + H] + , 266.0280; found, 266.0287.

[0116] The only difference from the preparation of compound b1 in Example 2 is that o-fluorothiophenol is replaced with m-trifluoromethylthiophenol. Compound b11 is obtained: 3-trifluoromethylphenyl dimethyl dithiocarbamate.

[0117]

[0118] White solid, yield: 85%; mp: 65-66 ℃; 1H NMR (400 MHz, Chloroform-d)δ 7.75 – 7.69 (m, 2H), 7.68 – 7.64 (m, 1H), 7.59 – 7.53 (m, 1H), 3.56 (s, 3H), 3.51 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 196.00, 140.43, 133.72 (q, J =3.8 Hz), 133.01, 131.38 (q, J = 32.7 Hz), 129.41, 126.75 (q, J = 3.7 Hz), 123.69 (q, J = 272.7 Hz), 45.75, 42.05. 19 F NMR (377 MHz, Chloroform-d) δ -62.60. HRMS (ESI) calculated for C 10 H 10 F3NS2 [M + H] + , 266.0280; found,266.0286.

[0119] The preparation of compound b1 differed from that in Example 2 only in that o-fluorothiophenol was replaced with p-trifluoromethylthiophenol. Compound b12 was obtained: 4-trifluoromethylphenyl dimethyl dithiocarbamate.

[0120]

[0121] White solid, yield: 91%; mp: 62-63 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.71 – 7.65 (m, 2H), 7.63 – 7.57 (m, 2H), 3.56 (s, 3H), 3.51 (s, 3H). 13 CNMR (101 MHz, Chloroform-d) δ 195.74, 137.21, 136.12, 131.81 (q, J = 32.6Hz), 125.89 (q, J = 3.7 Hz), δ 123.88 (q, J = 272.5 Hz), 45.70, 42.12. 19F NMR(377 MHz, Chloroform-d) δ -62.79. HRMS (ESI) calculated for C 10 H 10 F3NS2 [M + H] + , 266.0280; found, 266.0289.

[0122] The only difference from the preparation of compound b1 in Example 2 is that o-fluorothiophenol is replaced with o-methylthiophenol. Compound b13 is obtained: o-tolyl dimethyl dithiocarbamate.

[0123]

[0124] White solid, yield: 80%; mp: 53-54 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.46 – 7.31 (m, 3H), 7.30 – 7.21 (m, 1H), 3.55 (s, 3H), 3.52 (s, 3H) 2.41(s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 196.52, 143.90, 137.81, 131.23,130.80, 130.75, 126.78, 45.60, 42.07, 20.96. HRMS (ESI) calculated forC 10 H 13 NS2 [M + H] + , 212.0562; found, 212.0572.

[0125] The only difference from the preparation of compound b1 in Example 2 is that o-fluorothiophenol is replaced with m-methylthiophenol. Compound b14 is obtained: m-tolyl dimethyl dithiocarbamate.

[0126]

[0127] Yellow liquid, yield: 80%; 1 H NMR (400 MHz, Chloroform-d) δ 7.37 –7.32 (m, 1H), 7.31 – 7.26 (m, 3H), 3.56 (s, 3H), 3.50 (s, 3H), 2.39 (s, 3H).13 C NMR (101 MHz, Chloroform-d) δ 197.79, 138.92, 137.46, 134.04, 131.46,130.93, 128.97, 45.70, 42.07, 21.37. HRMS (ESI) calculated for C 10 H 13 NS2 [M +H] + , 212.0562; found, 212.0572.

[0128] The only difference from the preparation of compound b1 in Example 2 is that o-fluorothiophenol is replaced with p-methylthiophenol. Compound b15 is obtained: p-tolyl dimethyl dithiocarbamate.

[0129]

[0130] White solid, yield: 80%; mp: 70-71 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.38 – 7.32 (m, 2H), 7.28 – 7.22 (m, 2H), 3.55 (s, 3H), 3.49 (s, 3H), 2.40(s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 198.16, 140.41, 136.83, 130.04,128.35, 45.74, 41.97, 21.55. HRMS (ESI) calculated for C 10 H 13 NS2 [M + H] + ,212.0562; found, 212.0575.

[0131] The only difference from the preparation of compound b1 in Example 2 is that o-fluorothiophenol is replaced with o-methoxythiophenol. Compound b16 is obtained: 2-methoxyphenyl dimethyl dithiocarbamate.

[0132]

[0133] Light yellow solid, yield: 91%; mp: 77-78 ℃; 1H NMR (400 MHz, Chloroform-d) δ 7.54 – 7.45 (m, 1H), 7.45 – 7.38 (m, 1H), 7.07 – 6.98 (m, 2H), 3.86 (s, 3H), 3.55 (s, 3H), 3.52 (s, 3H). 13 C NMR (101 MHz, Chloroform-d)δ 196.76, 160.55, 138.85, 132.53, 121.21, 119.92, 111.96, 56.26, 45.70,42.11. HRMS (ESI) calculated for C 10 H 13 NOS2 [M + H] + , 228.0511; found,228.0523.

[0134] The preparation of compound b1 differed from that in Example 2 only in that o-fluorothiophenol was replaced with m-methoxythiophenol. Compound b17 was obtained: 3-methoxyphenyl dimethyl dithiocarbamate.

[0135]

[0136] White solid, yield: 80%; mp: 54-55 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.39 – 7.33 (m, 1H), 7.10 – 6.98 (m, 3H), 3.83 (s, 3H), 3.56 (s, 3H), 3.49(s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 197.30, 159.78, 132.57, 129.83,129.14, 122.00, 116.25, 55.43, 45.66, 42.05. HRMS (ESI) calculated forC 10 H 13 NOS2 [M + H] + , 228.0511; found, 228.0523.

[0137] The preparation of compound b1 differed from that in Example 2 only in that o-fluorothiophenol was replaced with p-methoxythiophenol. Compound b18 was obtained: 4-methoxyphenyl dimethyl dithiocarbamate.

[0138]

[0139] White solid, yield: 85%; mp: 87-88 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.41 – 7.34 (m, 2H), 7.00 – 6.93 (m, 2H), 3.84 (s, 3H), 3.56 (s, 3H), 3.49(s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 198.72, 161.14, 138.48, 122.62,114.76, 55.36, 45.82, 41.92. HRMS (ESI) calculated for C 10 H 13 NOS2 [M + H] + ,228.0511; found, 228.0524.

[0140] The only difference from the preparation of compound b1 in Example 2 is that o-fluorothiophenol was replaced with 3,5-difluorothiophenol. Compound b19 was obtained: 3,5-difluorophenyl dimethyl dithiocarbamate.

[0141]

[0142] White solid, yield: 84%; mp: 60-61 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.08 – 6.99 (m, 2H), 6.97 – 6.87 (m, 1H), 3.54 (s, 3H), 3.48 (s, 3H). 13 CNMR (101 MHz, Chloroform-d) δ 195.17, 162.55 (dd, J = 251.1, 12.6 Hz), 134.50 (t, J = 10.3 Hz), 120.19 – 119.77 (m), 105.88 (t, J = 25.1 Hz), 45.69, 42.10. 19F NMR (377 MHz, Chloroform-d) δ -109.08. HRMS (ESI) calculated for C9H9F2NS2[M + H] + , 234.0217; found, 234.0199.

[0143] The only difference from the preparation of compound b1 in Example 2 is that o-fluorothiophenol was replaced with 3,4-difluorothiophenol. Compound b20 was obtained: 3,4-difluorophenyl dimethyl dithiocarbamate.

[0144]

[0145] White solid, yield: 90%; mp: 59-60 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.35 – 7.27 (m, 1H), 7.26 – 7.17 (m, 2H), 3.55 (s, 3H), 3.48 (s, 3H). 13 CNMR (101 MHz, Chloroform-d) δ 196.24, 152.22 (dd, J = 170.2, 12.8 Hz), 149.71 (dd, J = 168.7, 12.8 Hz), 133.77 (dd, J = 6.6, 3.6 Hz), 127.98 (dd, J = 6.4,4.2 Hz), 126.18 (d, J = 17.8 Hz), 117.80 (d, J = 17.8 Hz), 45.78, 41.98. 19 FNMR (377 MHz, Chloroform-d) δ -134.36, -136.06. HRMS (ESI) calculated forC9H9F2NS2 [M + H] + , 234.0217; found, 234.0228.

[0146] The only difference from the preparation of compound b1 in Example 2 is that o-fluorothiophenol is replaced with 2,4-dichlorothiophenol. Compound b21 is obtained: 2,4-dichlorophenyldimethyl dithiocarbamate.

[0147]

[0148] Transparent solid, yield: 86%; mp: 56-57 ℃; 1 H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.35 –7.29 (m, 1H), 3.55 (s, 3H), 3.52 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ194.27, 141.38, 139.86, 137.38, 130.26, 129.68, 127.89, 45.68, 42.16. HRMS(ESI) calculated for C9H9Cl2NS2 [M + H] + , 265.9626; found, 265.9611.

[0149] The preparation of compound b1 differs from that of compound b1 in Example 2 only in that o-fluorothiophenol is replaced with 3,5-dichlorothiophenol. Compound b22 is obtained: 3,5-dichlorophenyldimethyl dithiocarbamate.

[0150]

[0151] Transparent solid yield: 84%; mp: 107-108 ℃; 1 H NMR (400 MHz, Chloroform-d) δ 7.47 – 7.43 (m, 1H), 7.39 – 7.34 (m, 2H), 3.55 (s, 3H), 3.48 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 195.10, 135.07, 134.89, 134.50,130.17, 45.75, 42.12. HRMS (ESI) calculated for C9H9Cl2NS2 [M + H] + , 265.9626;found, 265.9613.

[0152] The only difference from the preparation of compound b1 in Example 2 is that o-fluorothiophenol was replaced with 3,4-dichlorothiophenol. Compound b23 was obtained: 3,4-dichlorophenyldimethyl dithiocarbamate.

[0153]

[0154] Light yellow solid, yield: 85%; mp: 71-72 ℃; 1 H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.33 –7.26 (m, 1H), 3.54 (s, 3H), 3.48 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ195.67, 138.39, 136.21, 134.76, 132.79, 131.57, 130.84, 45.79, 42.09. HRMS(ESI) calculated for C9H9Cl2NS2 [M + H] + , 265.9626; found, 265.9634.

[0155] The preparation of compound b1 differs from that in Example 2 only in that o-fluorothiophenol is replaced with 3,5-bis(trifluoromethyl)thiophenol. Compound b24 is obtained: 3,5-bis(trifluoromethyl)phenyl dimethyl dithiocarbamate.

[0156]

[0157] White solid, yield: 70%; mp: 63-64 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.97 – 7.88 (m, 3H), 3.56 (s, 3H), 3.52 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 194.33, 137.10 (q, J = 3.8 Hz), 134.77, 132.05 (q, J = 33.8Hz), 123.66 (q, J = 3.8 Hz), 122.96 (q, J = 273.1 Hz), 45.80, 42.06. 19 F NMR(377 MHz, Chloroform-d) δ -62.85. HRMS (ESI) calculated for C 11H9F6NS2 [M + H] + , 334.0153; found, 334.0168.

[0158] Example 3: Preparation of compounds b25-b28

[0159] General synthetic method: Methyl isothiocyanate (1.0 mmol, 1.0 equivalent), the corresponding substituted thiophenol (1.0 mmol, 1.0 equivalent), and sodium bicarbonate (1.05 mmol, 1.05 equivalent) were placed in a dry reaction flask, with anhydrous ethanol (10 mL) as the solvent. The suspension was stirred at room temperature for 1 h, and the reaction progress was monitored by TLC. After the reaction was completed, 20 mL of saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by thin-layer chromatography (dichloromethane / petroleum ether = 1:1) to obtain the target compound.

[0160] The only difference from Example 2 is that methyl isothiocyanate was used instead of dimethylcarbamoyl chloride, p-fluorothiophenol was used as the raw material, ethanol was used as the solvent, and the reaction was carried out at room temperature for 1 hour. Compound b25: 4-fluorophenylmethyl dithiocarbamate was obtained.

[0161]

[0162] White solid, yield: 65%; mp: 125-126 ℃; 1 H NMR (400 MHz, Chloroform-d) δ 7.65 – 7.56 (m, 2H), 7.25 – 7.16 (m, 2H), 6.69 (s, 1H), 3.16 (d, J = 4.7Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 195.78, 164.38 (d, J = 253.6 Hz), 138.09 (d, J = 8.8 Hz), 124.27 (d, J = 3.6 Hz), 117.77 (d, J = 22.0 Hz), 33.58. 19 F NMR (377 MHz, Chloroform-d) δ -107.51. RMS (ESI) calculated forC8H8FNS2 [M + H] + , 202.0155; found, 202.0141.

[0163] The only difference from Example 2 is that methyl isothiocyanate was used instead of dimethylcarbamoyl chloride, p-chlorothiophenol was used as the raw material, ethanol was used as the solvent, and the reaction was carried out at room temperature for 1 hour. Compound b26: 4-chlorophenylmethyl dithiocarbamate was obtained.

[0164]

[0165] White solid, yield: 65%; mp: 92-93 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.55 – 7.44 (m, 4H), 6.70 (s, 1H), 3.15 (d, J = 4.8 Hz, 3H). 13 C NMR (101MHz, Chloroform-d) δ 195.31, 137.85, 137.03, 130.70, 127.24, 33.60. HRMS(ESI) calculated for C8H8ClNS2 [M + H] + , 217.9858; found, 217.9862.

[0166] The only difference from Example 2 is that methyl isothiocyanate was used instead of dimethylcarbamoyl chloride, p-bromothiophenol was used as the raw material, ethanol was used as the solvent, and the reaction was carried out at room temperature for 1 hour. Compound b27: 4-bromophenylmethyl dithiocarbamate was obtained.

[0167]

[0168] White solid, yield: 68%; mp: 117-118 ℃; 1 H NMR (400 MHz, Chloroform-d) δ 7.68 – 7.59 (m, 2H), 7.48 – 7.40 (m, 2H), 6.71 (s, 1H), 3.14 (d, J = 4.8Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 195.12, 137.20, 133.68, 127.81,126.21, 33.63. HRMS (ESI) calculated for C8H8BrNS2 [M + H] + , 261.9354; found,261.9353.

[0169] The only difference from Example 2 is that methyl isothiocyanate was used instead of dimethylcarbamoyl chloride, p-trifluoromethylthiophenol was used as the raw material, ethanol was used as the solvent, and the reaction was carried out at room temperature for 1 hour. Compound b28: 4-trifluoromethylphenylmethyl dithiocarbamate was obtained.

[0170]

[0171] White solid, yield: 60%; mp: 96-97 ℃; 1 H NMR (400 MHz, Chloroform-d)δ 7.78 – 7.67 (m, 4H), 6.81 (s, 1H), 3.16 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 194.46, 136.02, 133.39, 132.81 (q, J = 33.0 Hz), 127.11 (q, J= 3.7 Hz), 123.49 (q, J = 272.8 Hz), 33.73. 19 F NMR (377 MHz, Chloroform-d) δ-62.15. HRMS (ESI) calculated for C8H8F3NS2 [M + H] + , 252.0123; found,252.0113.

[0172] Example of effect verification:

[0173] The antifungal activity of the thiocarbamate derivatives prepared in the embodiments of the present invention was studied:

[0174] Experimental subjects: compounds a1-a15 and b1-b28, with thiram as a positive control;

[0175] Experimental methods: The linear mycelial growth rate method was used to determine the in vitro inhibitory activity against 10 tested plant pathogenic fungi, including *Valsa mali* (causing apple rot), *Sclerotinia sclerotiorum* (causing sclerotiorum), *Botrytis cinerea* (causing gray mold), *Rhizoctonia solani* (causing sclerotiorum solani), *Alternaria alternata* (causing alternata), *Fusarium graminearum* (causing wheat scab), *Pythium graminicola* (causing graminicola), *Curvularia lunata* (causing crescenticulata), *Phytophthora capsici* (causing pepper sclerotium), and *Sclerotium rolfsii* (causing uniform sclerotium).

[0176] Preliminary screening was conducted at a concentration of 40 mg / L. The test compound was completely dissolved in a 5% DMSO aqueous solution, and the test solution was rapidly mixed with PDC medium to obtain the drug-containing medium. The medium was poured into sterilized petri dishes and cooled for later use. The tested plant pathogenic fungi (cup diameter 5 mm) were inoculated into the above petri dishes, with 3 replicates for each test group. After incubation at 25℃ for 72 h, the colony diameter (mm) was measured using the cross-crossing method, and the mycelial growth inhibition rate was calculated.

[0177] IR(%) = [(d c - d o ) - (d s - d o )] / (d c - d o Formula (1) is 100 × 100.

[0178] The measurement results are shown in the table below.

[0179]

[0180]

[0181]

[0182] Analysis of activity screening results:

[0183] Preliminary bioassays revealed the in vitro inhibitory activity profiles of the target compounds against ten plant pathogenic fungi and oomycetes. We synthesized a total of 43 compounds and conducted preliminary antifungal activity tests against 10 plant pathogenic fungi at a concentration of 40 mg / L, using thiram as a positive control. The results showed that the a-series and b-series compounds generally exhibited excellent antifungal activity against *S. rolfsii*. Most compounds showed inhibition rates exceeding 80% against *S. rolfsii*. Compounds a6, a9, a12, b3, b6, b9, b12, b15, b18, and b20 achieved 100% inhibition against *S. rolfsii*. Compounds b5, b6, b8, b11, b12, b19, b20, b21, and b23 showed superior inhibitory activity against *S. rolfsii* (the causal agent of apple rot) compared to the positive control thiram (82.0%). Notably, compounds b6 and b12 exhibited significant broad-spectrum fungicidal activity, with inhibition rates exceeding 90% against *Phytophthora indica*, *Sclerotinia sclerotiorum*, *Botrytis cinerea*, *Phytophthora capsici*, and *Sclerotium sclerotiorum*. Furthermore, under the same substituent conditions, compounds containing sulfur atoms generally showed better antifungal activity than those containing oxygen atoms. The activity of para-substituents on the benzene ring was superior to that of substituents at other positions. To explore whether exposing nitrogen-hydrogen bonds enhanced compound activity, we synthesized four compounds containing nitrogen-hydrogen bonds (b25-b28), but the antifungal activity results indicated that exposing a single NH group did not enhance their antifungal activity.

[0184] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A thiocarbamate derivative, characterized in that... Its general structural formula is shown in Equation I below: ； Among them, R 1 It is one or more of halogen, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy; R 2 For methyl, R 3 It is H or methyl, and X is O or S atom.

2. The method for preparing the thiocarbamate derivative according to claim 1, characterized in that: Using substituted phenol or substituted thiophenol 1 and compound 2 as reaction substrates, the target product, a thiocarbamate derivative, was prepared by reacting in a solvent system containing an alkali. The reaction route is shown below: 。 3. The preparation method according to claim 2, characterized in that: The alkali is sodium hydride or sodium bicarbonate.

4. The preparation method according to claim 2 or 3, characterized in that... Includes the following steps: Dimethylaminothioformyl chloride 2, substituted phenol or substituted thiophenol 1, and sodium hydride were added to a dry reaction flask and reacted at 80°C using N,N-dimethylformamide as solvent. After the reaction was completed, the residue was dissolved in a saturated ammonium chloride solution and then extracted with ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain the target product.

5. The preparation method according to claim 4, characterized in that: The substituted phenol is selected from one of o-fluorophenol, m-fluorophenol, p-fluorophenol, o-chlorophenol, m-chlorophenol, p-chlorophenol, o-bromophenol, m-bromophenol, p-bromophenol, o-trifluoromethylphenol, m-trifluoromethylphenol, p-trifluoromethylphenol, o-methoxyphenol, m-methoxyphenol, and p-methoxyphenol. The substituted thiophenol is selected from one of o-fluorothiophenol, m-fluorothiophenol, p-fluorothiophenol, o-chlorothiophenol, m-chlorothiophenol, p-chlorothiophenol, o-bromothiophenol, m-bromothiophenol, p-bromothiophenol, o-trifluoromethylthiophenol, m-trifluoromethylthiophenol, p-trifluoromethylthiophenol, o-methylthiophenol, m-methylthiophenol, p-methylthiophenol, o-methoxythiophenol, m-methoxythiophenol, p-methoxythiophenol, 3,5-difluorothiophenol, 3,4-difluorothiophenol, 2,4-dichlorothiophenol, 3,5-dichlorothiophenol, 3,4-dichlorothiophenol, and 3,5-bistrifluoromethylthiophenol.

6. The preparation method according to claim 2 or 3, characterized in that... Includes the following steps: Methyl isothiocyanate 2, substituted phenol or substituted thiophenol 1, and sodium bicarbonate were added to a dry reaction flask and reacted at room temperature using anhydrous ethanol as solvent. After the reaction was completed, the residue was dissolved in a saturated ammonium chloride solution and then extracted with ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin-layer chromatography to obtain the target product.

7. The preparation method according to claim 6, characterized in that: The substituted thiophenol is selected from one of p-fluorothiophenol, p-chlorothiophenol, p-bromothiophenol, and p-trifluoromethylthiophenol.

8. The use of the thiocarbamate derivative of claim 1 in the preparation of antifungal drugs.

9. The application according to claim 8, characterized in that: The fungi include one or more of the following: apple rot fungus, sclerotium rot fungus, gray mold fungus, rhizoctonia solani fungus, Alternaria alternata, wheat scab, Pythium graminearum, Curvularia crescentis, Phytophthora capsici, and Sclerotium sclerotiorum.

10. An antifungal drug, characterized in that: The active pharmaceutical ingredient is a thiocarbamate derivative as described in claim 1; the fungus includes one or more of the following: apple rot fungus, sclerotium rot fungus, gray mold fungus, rhizoctonia solani fungus, Alternaria alternata, wheat scab, Pythium graminearum, Curvularia crescentis, Phytophthora capsici, and Sclerotium sclerotiorum.

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