4-Substituted-5h-1,2,3-dithiazole-5-thiones and derivatives synthesis

Abstract

The present application relates to a kind of 4-substituted-5H-1,2,3-dithiazole-5-thione and derivative and its synthesis method.The present application uses in non-metal iodine compound catalysis, methyl ketone compound, nitrogen-containing small molecule and elemental sulfur are converted into the technical scheme of 4-substituted-5H-1,2,3-dithiazole-5-thione and derivative.This technical scheme has the following advantages: the reagent required stable nature, need not pretreatment, cheap and easy to obtain;One-pot synthesis, the economy advantage of step is obvious, save time and effort;Without using transition metal catalysis, metal residue problem is eliminated from the root;Using cheap iodine compound catalysis, reduce environmental pollution, save reaction cost;Cheap and easy to obtain, safe and stable nitrogen-containing small molecule provides nitrogen source, elemental sulfur provides sulfur source, elemental sulfur provides two types of structures of per-sulfur bond and carbon-sulfur double bond in reaction;Whole reaction system is simple, reaction equipment is less, and operation is simple;The 4-substituted-5H-1,2,3-dithiazole-5-thione synthesized has good biological activity function, is potential drug molecule.

Description

Technical Field

[0001] This invention relates to a method for synthesizing 4-substituted-5H-1,2,3-dithiazol-5-thione and its derivatives, belonging to the field of organic compound synthesis technology. Background Technology

[0002] 1,2,3-Dithiazole-5-thione and its derivatives constitute an important class of nitrogen-containing polysulfide heterocyclic compounds. As an important subclass of thiazole compounds, this skeletal molecule contains both a "-S2-" bond and a "C=S" double bond. This unique nitrogen-containing polysulfide five-membered ring structure endows 1,2,3-dithiazole-5-thione compounds with excellent biological activities, including antibacterial and antitumor activities (Bioorg. Med. Chem. Lett. 2009, 19, 136–141, DOI:10.1016 / j.bmcl.2008.11.010). They can also be used as inhibitors of feline immunodeficiency virus (FIV) (ChemMedChem). The 2016,11,2119-2126,DOI:10.1002 / cmdc.201600260) and anticancer drug molecules (Bioorg.Med.Chem.Lett.2021,43,128078,DOI:10.1016 / j.bmcl.2021.128078) have shown great potential for application in the pharmaceutical field.

[0003] To date, the synthetic methods for 4-substituted-5H-1,2,3-dithiazol-5-thione have the following drawbacks: (1) They are synthesized from oxime compounds, but the oxime compounds need to be prepared in advance, and a five-membered ring is constructed using stoichiometrically unstable and highly toxic disulfide / pyridine reagent under argon protection. Finally, the 1,2,3-dithiazol-5-thione compound is synthesized by generating C=S bonds under thioacetamide sulfidation. The reaction needs to be prepared under an inert atmosphere, at low temperature, and in multiple steps; (2) They use highly functionalized... (2) Polychlorinated 1,2,3-dithiazolium salts were used as starting materials to prepare the product under the action of malodorous H2S; (3) Oxime esters were used as raw materials to synthesize the product under copper salt catalysis, but the reaction yield was not ideal; (4) Elemental sulfur, acetophenone and ammonium acetate were used as raw materials to synthesize the product by heating in dimethyl sulfoxide solution, but the reaction yield was extremely low, and only trace products were detected by gas chromatography-mass spectrometry (according to Chemische Berichte, 1985, 118, 1632-1643; ChemMedChem). (2016, 11, 2119-2126; Org. Biomol. Chem., 2019, 17, 3424-3432 and RSC Adv., 2021, 11, 3890-3890) Therefore, it is essential to develop a synthetic method for the one-pot synthesis of 4-substituted-5H-1,2,3-dithiazol-5-thione compounds using simple and inexpensive starting materials under transition metal-free conditions. Summary of the Invention

[0004] This invention provides a method for synthesizing 4-substituted-5H-1,2,3-dithiazol-5-thione and its derivatives.

[0005] The technical solution adopted by this invention to solve its technical problem is as follows: This invention provides a 4-substituted-5H-1,2,3-dithiazol-5-thione and its derivatives, the general formula of which is Formula I:

[0006]

[0007] in

[0008] R is selected from: C1-C10 straight-chain alkyl, branched alkyl, cyclic alkyl, adamantyl; substituted or unsubstituted C6-C30 aryl, benzyl, benzenesulfonyl, benzoyl; substituted or unsubstituted heterocyclic groups containing nitrogen, oxygen, and sulfur atoms; substituents are selected from C1-C10 straight-chain alkyl, branched alkyl, cyclic alkyl, halogen, nitro, amino, hydroxyl, methoxy, phenyl, sulfone, ester, aldehyde, trifluoromethyl.

[0009] The synthesis method is as follows: using an iodine-containing compound as a catalyst, a sulfoxide compound as a co-oxidizing agent, a nitrogen-containing small molecule as a nitrogen source, and elemental sulfur as a sulfur source, including the following synthesis steps:

[0010] Add methyl ketone compounds, nitrogen-containing small molecules, elemental sulfur, catalysts, sulfoxide compounds and organic solvents;

[0011] After thoroughly mixing the reactants, heat the mixture to react.

[0012] The product was obtained after purification.

[0013] Preferably, in the synthesis method of the present invention, the methyl ketone compound is selected from C7-C30 methyl ketone compounds, and its general formula is Formula II:

[0014]

[0015] Preferably, in the synthesis method of the present invention, the methyl ketone compound is selected from: acetophenone, p-methylacetophenone, p-ethylacetophenone, p-propylacetophenone, p-tert-butylacetophenone, p-pentylacetophenone, p-cyclohexylacetophenone, p-morpholinoacetophenone, p-methoxyacetophenone, p-methylthioacetophenone, p-hydroxyacetophenone, p-phenylacetophenone, p-trifluoromethylacetophenone, methyl formate acetophenone, p-fluoroacetophenone, p-chloroacetophenone, p-bromoacetophenone, p-iodoacetophenone, p-cyanoacetophenone, p-nitroacetophenone, p-methylsulfonylacetophenone, m-methylacetophenone, m-methoxyacetophenone, m-fluoroacetophenone, and m-chloroacetophenone. m-Bromoacetophenone, m-Trifluoromethylacetophenone, m-Nitroacetophenone, o-Methylacetophenone, o-Methoxyacetophenone, o-Fluoroacetophenone, o-Chloroacetophenone, o-Bromoacetophenone, 3,4-Dimethoxyacetophenone, 3,4-Difluoroacetophenone, 3,4-Dichloroacetophenone, 3-Methyl-4-chloroacetophenone, 1-Acetylnaphthalene, 2-Acetylnaphthalene, 2-Acetylfuran, 2-Acetylthiophene, 3-Acetylthiophene, 4-Acetylpyridine, 2-Acetylbenzofuran, 2-Acetylbenzothiophene, 3-Acetylphenanthrene, 2-Pentanone, Methyl tert-Butylketone, Acetylcyclohexane, 1-Acetylphosphonane.

[0016] Preferably, in the synthesis method of the present invention, the nitrogen-containing small molecule has one of the following structural formulas:

[0017]

[0018] in

[0019] X is selected from: fluoride ion; chloride ion; bromide ion; iodide ion; sulfate ion; sulfite ion; bisulfate ion; hydroxide ion; carbonate ion; bicarbonate ion; nitrate ion; acetate ion; sulfide ion; thiocyanate ion.

[0020] R 1 Selected from: methoxy, phenylamino, benzyl, cyano, benzenesulfonyl, formamido, benzoyl, thiobenzoyl.

[0021] R2 Selected from: C1-C3 straight-chain alkyl, branched alkyl; substituted or unsubstituted C6-C7 aryl, benzyl.

[0022] R 3 Selected from: C1-C3 straight-chain alkyl and branched-chain alkyl.

[0023] R 4 Selected from: C1-C4 straight-chain alkyl, branched-chain alkyl; methoxy.

[0024] Preferably, in the synthesis method of the present invention, the nitrogen-containing small molecule is selected from one or more of the following: ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, ammonium sulfate, ammonium sulfite, ammonium bisulfate; ammonium carbonate; ammonium bicarbonate; ammonium nitrate; ammonium acetate; aqueous solution of ammonium sulfide, ammonium thiocyanate, hydroxylamine hydrochloride, methoxyamine hydrochloride, phenylhydrazine, benzylamine, cyanamide, benzylsulfonamide, formylhydrazine, benzoylhydrazine, phenylthioformylhydrazine, ethylenediamine, propylenediamine, diphenylamine, dibenzylamine, triethylamine, tripropylamine, tetrabutylammonium bisulfate, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium fluoride trihydrate, tetrabutylammonium hydroxide, tetrabutylammonium chloride, tetrabutylammonium acetate, tetramethylammonium iodide, and tetramethoxyammonium chloride.

[0025] Preferably, in the synthesis method of the present invention, the iodine-containing compound is selected from one or more of the following: elemental iodine, hydroiodic acid, potassium iodide, sodium iodide, ammonium iodide, iodine chloride, iodine bromide, iodine trichloride, N-iodosuccinimide, tetramethylamine iodide, tetrabutylammonium iodide, potassium iodate, sodium periodate, hydroxytoluenesulfonyl iodobenzene, [bis(trifluoroacetoxy)iodo]benzene, iodophenyldiacetic acid, and trimethyl sulfoxide.

[0026] Preferably, in the synthesis method of the present invention, the sulfoxide compound is selected from one or more of dimethyl sulfoxide, dibutyl sulfoxide, methyl phenyl sulfoxide, dibenzyl sulfoxide, diphenyl sulfoxide, and tetramethylene sulfoxide.

[0027] Preferably, in the synthesis method of the present invention, the reaction atmosphere is: air atmosphere; the molar ratio of methyl ketone compound, nitrogen-containing small molecule, elemental sulfur, sulfoxide compound and iodine-containing catalyst is 1.0-10.0:2.0-30.0:4.0-40.0:3.0-40.0:0.2-5.0; simultaneously, the reaction temperature is 125℃-140℃; the reaction time is 2h-24h; and the organic solvent is one or more of 1,4-dioxane and ethylene glycol dimethyl ether.

[0028] The beneficial effects of this invention compared to the prior art are as follows:

[0029] (I) This invention is the first to adopt a technical solution in which sulfoxide compounds are used as oxidants under the catalysis of iodine-containing compounds to convert methyl ketone compounds, nitrogen-containing small molecules and elemental sulfur into 4-substituted-5H-1,2,3-dithiazol-5-thione and its derivatives in an air atmosphere, so as to obtain products with stable molecular structure and excellent chemical properties and their by-products.

[0030] (II) A technical solution for converting methyl ketone compounds, nitrogen-containing small molecules and elemental sulfur into 4-substituted-5H-1,2,3-dithiazol-5-thione and its derivatives in an air atmosphere under the catalysis of iodine-containing compounds and the use of sulfoxide compounds as pro-oxidants. The reaction raw materials are inexpensive and readily available, and no pretreatment is required. The reaction has high atom economy.

[0031] (III) A technical solution for converting methyl ketone compounds, nitrogen-containing small molecules, and elemental sulfur into 4-substituted-5H-1,2,3-dithiazol-5-thione and its derivatives in an air atmosphere under the catalysis of iodine-containing compounds and with sulfoxide compounds as pro-oxidants. The reaction does not require metal catalysts or equivalent amounts of metal oxidants or ligands. Only iodine-containing compounds are needed, saving raw materials and reducing reaction costs.

[0032] (IV) A technical solution that uses sulfoxide compounds as a co-oxidant to convert methyl ketone compounds, nitrogen-containing small molecules and elemental sulfur into 4-substituted-5H-1,2,3-dithiazol-5-thione and its derivatives in an air atmosphere under the catalysis of iodine-containing compounds. This solution adopts a one-pot direct selective synthesis of the target product with high yield, overcomes the huge waste of human, financial and material resources caused by multi-step synthesis methods, and saves a lot of research and development time and production cycle.

[0033] (V) A technical solution that uses sulfoxide compounds as a co-oxidant under the catalysis of iodine-containing compounds to convert methyl ketone compounds, nitrogen-containing small molecules and elemental sulfur into 4-substituted-5H-1,2,3-dithiazol-5-thione and its derivatives in an air atmosphere. This solution overcomes the high product implementation cost caused by existing multi-step synthesis methods, thereby greatly advancing the actual application of the product and creating the basic conditions for early industrial production.

[0034] (VI) A technical solution for converting methyl ketone compounds, nitrogen-containing small molecules and elemental sulfur into 4-substituted-5H-1,2,3-dithiazol-5-thione and its derivatives in an air atmosphere under the catalysis of iodine-containing compounds and with sulfoxide compounds as pro-oxidants is scientific, reasonable, easy to operate, has few reaction steps and requires few equipment.

[0035] (VII) A technical solution that converts methyl ketone compounds, nitrogen-containing small molecules and elemental sulfur into 4-substituted-5H-1,2,3-dithiazol-5-thione and its derivatives in an air atmosphere under the catalysis of iodine-containing compounds and with sulfoxide compounds as pro-oxidants has the advantages of wide range of reaction raw materials, low input, high output, and easy to further mass production and popularization.

[0036] (VIII) A technical solution for converting methyl ketone compounds, nitrogen-containing small molecules, and elemental sulfur into 4-substituted-5H-1,2,3-dithiazol-5-thione and its derivatives in an air atmosphere under the catalysis of iodine-containing compounds and with sulfoxide compounds as pro-oxidants has the advantages of a simple reaction system, mild reaction conditions, inexpensive and stable nitrogen-containing small molecules as nitrogen sources, elemental sulfur as sulfur sources, simple and safe experimental operation, wide availability of raw materials, easy expansion of users and applications, high product utilization value, and promising market commercialization prospects.

[0037] This invention relates to 4-substituted-5H-1,2,3-dithiazol-5-thione and its derivatives, as well as their synthetic methods, which can be applied in the pharmaceutical field; it is particularly suitable for the research and development of efficient one-pot synthesis of 4-substituted-5H-1,2,3-dithiazol-5-thione and its derivatives without metal catalysis and using a multi-component method. Attached Figure Description

[0038] To demonstrate the product of this invention, the present invention provides NMR hydrogen and NMR carbon spectra of some embodiments. a is the hydrogen spectrum, and b is the carbon spectrum.

[0039] Figure 1a and 1b The NMR spectrum of the product of Example 1; Figure 2a and 2b The NMR spectrum of the product of Example 6;

[0040] Figure 3a and 3b The NMR spectrum of the product of Example 8; Figure 4a and 4b The NMR spectrum of the product of Example 10;

[0041] Figure 5a and 5b The NMR spectrum of the product of Example 15; Figure 6a and 6b The NMR spectrum of the product of Example 22;

[0042] Figure 7a and 7b The NMR spectrum of the product of Example 25; Figure 8a and 8b The NMR spectrum of the product of Example 30;

[0043] Figure 9a and 9b The NMR spectrum of the product of Example 33; Figure 10a and 10b The NMR spectrum of the product of Example 34;

[0044] Figure 11a and 11b The NMR spectrum of the product of Example 37; Figure 12a and 12b The NMR spectrum of the product of Example 38;

[0045] Figure 13a and 13b The NMR spectrum of the product of Example 40; Figure 14a and 14b The NMR spectrum of the product of Example 49;

[0046] Figure 15 This is a schematic diagram of the reaction equation of this application. Detailed Implementation

[0047] The present invention will now be described in further detail with reference to the accompanying drawings. These drawings are simplified schematic diagrams, illustrating only the basic structure of the invention, and therefore only show the components relevant to the invention.

[0048] The schematic diagram of the reaction equation is as follows Figure 15 As shown:

[0049] Where air is air (but there is no need to limit the gas atmosphere; nitrogen or argon environments are also acceptable).

[0050] Examples 1-50

[0051] Step 1: Add methyl ketone compounds (specific substances are shown in Table 1), nitrogen-containing small molecules (specific substances are shown in Table 1), sulfoxide compounds (specific substances are shown in Table 1), and elemental sulfur to the reaction vessel. Add the solution of iodine-containing compounds (specific substances are shown in Table 1) to the reaction vessel. Alternatively, iodine-containing compounds (specific substances are shown in Table 1) and organic solvents (specific substances are shown in Table 1) can be added to the vessel separately.

[0052] Step 2: Heat the reaction vessel uniformly (e.g., in an oil bath) to the temperature described in Table 1. The methyl ketone compound, elemental sulfur, and nitrogen-containing small molecules react in the solvent for the time described in Table 1.

[0053] Step 3: Separation and purification.

[0054] Table 1: Molar ratios, reaction temperatures, and reaction times of methyl ketone compounds, nitrogen-containing small molecules, sulfoxide compounds, iodine-containing compounds, organic solvents, and (methyl ketone compounds, nitrogen-containing small molecules, elemental sulfur, sulfoxide compounds, and iodine-containing compounds) in Examples 1-50.

[0055]

[0056]

[0057]

[0058]

[0059]

[0060] * indicates the molar ratio of methyl ketone compounds, nitrogen-containing molecules, elemental sulfur, sulfoxide compounds, and iodine-containing compounds.

[0061] In the reactions described above, the methyl ketone compound first undergoes in-situ oxidation with the co-oxidation of iodide and sulfoxide compounds to generate benzoylformaldehyde. Benzoylformaldehyde then undergoes intermolecular dehydration condensation with nitrogen-containing small molecules to form an imine intermediate. Subsequently, elemental sulfur and the imine intermediate undergo a Willgerodt-Kindler type oxidation process to yield a polysulfide intermediate. Finally, the polysulfide intermediate releases small molecules to obtain the target compound.

[0062] The conversion rate of the substances in the reaction vessel after step 3 was detected and nuclear magnetic resonance (NMR) tests were performed. The results of some embodiments are as follows:

[0063] NMR data of the product from Example 1: 1 H NMR(500MHz,Chloroform-d)δ7.83(d,2H),7.46–7.27(m,3H); 13 C NMR (126MHz, CDCl3) δ208.2,168.0,131.5,130.5,129.5,128.1.

[0064] NMR data of the product from Example 2: 1 H NMR (500MHz, Chloroform-d) δ7.82 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 7.7 Hz, 2H), 2.41 (s, 3H); 13 C NMR (126MHz, CDCl3) δ208.4,167.9,140.9,129.4,128.8,128.6,21.5.

[0065] NMR data of the product from Example 3: 1H NMR (500MHz, Chloroform-d) δ7.85 (d, J = 8.3Hz, 2H), 7.29 (d, J = 8.0Hz, 2H), 2.71 (q, J = 7.6Hz, 2H), 1.27 (t, J = 7.6Hz, 3H); 13 C NMR (126MHz, CDCl3) δ208.4,167.9,147.1,129.4,128.8,127.6,28.8,15.2.

[0066] NMR data of the product from Example 4: 1 H NMR(500MHz,Chloroform-d)δ7.85(d,J=7.9Hz,2H),7.26(d,J=8.0Hz,2H),2.64(t,J=7.6Hz,2H),1.73–1.58(m,2H),0.96(t,J=7.3Hz,3H); 13 C NMR (126MHz, CDCl3) δ208.3,167.9,145.6,129.3,128.8,128.2,37.9,24.2,13.8.

[0067] NMR data of the product from Example 5: 1 H NMR (500MHz, Chloroform-d) δ7.89 (d, J = 8.2Hz, 2H), 7.40 (d, 2H), 1.35 (s, 9H); 13 C NMR (126MHz, CDCl3) δ208.3,167.8,153.9,129.2,128.6,125.1,34.9,31.2.

[0068] NMR data of the product from Example 6: 1 H NMR(500MHz,Chloroform-d)δ7.85(d,J=8.1Hz,2H),7.26(d,J=8.1Hz,2H),2.6 5(t,J=7.8Hz,2H),1.83–1.61(m,2H),1.45–1.20(m,4H),0.89(t,J=6.6Hz,3H); 13 C NMR (126MHz, CDCl3) δ208.3,167.9,145.9,129.3,128.7,128.1,35.9,31.5,30.8,22.5,14.0.

[0069] NMR data of the product from Example 7: 1H NMR(500MHz,Chloroform-d)δ7.86(d,J=8.0Hz,2H),7.29(d,J=8.0Hz,2H),2.70–2.41(m,1H),2.01–1.73(m,4H),1.43(m,4H),1.33–1.20(m,2H); 13 C NMR (126MHz, CDCl3) δ208.3,167.8,150.8,129.4,128.9,126.6,44.5,34.2,26.8,26.1.

[0070] NMR data of the product from Example 8: 1 H NMR(500MHz,Chloroform-d)δ7.97(d,J=8.9Hz,2H),6.92(d,J=8.6Hz,2H),3.90–3.83(m,4H),3.31–3.22(m,4H); 13 C NMR (126MHz, CDCl3) δ208.6,167.2,152.5,130.7,122.1,113.8,66.7,48.0.

[0071] NMR data of the product from Example 9: 1 H NMR (500MHz, Chloroform-d) δ7.88 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 3.78 (s, 3H); 13 C NMR (126MHz, CDCl3) δ208.4,167.3,161.4,131.1,123.9,113.5,55.3.

[0072] NMR data of the product from Example 10: 1 H NMR(500MHz,Chloroform-d)δ7.90(d,J=8.5Hz,2H),7.28(d,J=8.5Hz,2H),2.52(s,3H); 13 C NMR (126MHz, CDCl3) δ208.1,167.1,142.4,129.7,127.7,125.1,15.1.

[0073] NMR data of the product from Example 11: 1 H NMR (500MHz, DMSO-d6) δ10.00 (s, 1H), 7.80 (d, J = 8.7Hz, 2H), 6.84 (d, J = 8.7Hz, 2H); 13C NMR (126MHz, DMSO-d6) δ209.3,167.8,159.8,131.3,122.9,115.2.

[0074] NMR data of the product from Example 12: 1 H NMR (500MHz, Chloroform-d) δ8.03(d,J=8.1Hz,1H),7.68(d,J=8.0Hz,2H),7.63(d,J=7.7Hz,2H),7.46(t,J=7.7Hz,3H),7.38(t,J=7.4Hz,1H); 13 C NMR (126MHz, CDCl3) δ208.2,167.5,143.3,140.1,130.3,129.9,128.9,127.9,127.2,126.8

[0075] NMR data of the product from Example 13: 1 H NMR (500MHz, Chloroform-d) δ8.00–7.88 (m, 2H), 7.14 (t, J = 8.7Hz, 2H); 13 C NMR (126MHz, Chloroform-d) δ207.9, 166.7, 164.0 (d, J = 251.9Hz), 131.7 (d, J = 8.6Hz), 127.5 (d, J = 3.4Hz), 115.2 (d, J = 21.8Hz).

[0076] NMR data of the product in Example 14: 1 H NMR (500MHz, Chloroform-d) δ7.9 (d, J = 8.5 Hz, 2H), 7.4 (d, J = 8.6 Hz, 2H); 13 C NMR (126MHz, CDCl3) δ207.7,166.6,147.2,136.8,130.8,128.4.

[0077] NMR data of the product from Example 15: 1 H NMR (500MHz, Chloroform-d) δ7.84 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H); 13 C NMR (126MHz, CDCl3) δ207.7,166.7,131.4,131.0,130.3,125.2.

[0078] NMR data of the product from Example 16: 1H NMR (500MHz, Chloroform-d) δ7.80 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 8.5 Hz, 2H); 13 C NMR (126MHz, CDCl3) δ207.7,166.8,137.4,131.0,130.9,97.5.

[0079] NMR data of the product from Example 17: 1 H NMR (500MHz, Chloroform-d) δ8.06 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 8.1 Hz, 2H); 13 C NMR (126MHz, Chloroform-d) δ207.5, 166.4, 134.8, 132.2 (q, J = 32.9Hz), 129.9, 125.1 (q, J = 3.8Hz), 123.7 (q, J = 272.5Hz).

[0080] NMR data of the product from Example 22: 1 H NMR (500MHz, Chloroform-d) δ7.70(d,J=7.8Hz,1H),7.68(s,1H),7.34(t,J=7.6Hz,1H),7.32–7.28(m,1H),2.40(s,3H); 13 C NMR (126MHz, CDCl3) δ208.3,168.2,137.9,131.3,131.3,130.0,128.0,126.5,21.4.

[0081] NMR data of the product from Example 23: 1 H NMR(500MHz,Chloroform-d)δ7.51–7.46(m,2H),7.37(t,J=7.9Hz,1H),7.06–7.00(m,1H),3.84(s,3H); 13 C NMR (126MHz, CDCl3) δ208.1,167.5,159.1,132.5,129.2,121.9,116.6,114.7,55.4.

[0082] NMR data of the product from Example 24: 1 H NMR(500MHz,Chloroform-d)δ7.74(d,J=7.8Hz,1H),7.70(d,J=10.0Hz,1H),7.47–7.38(m,1H),7.19(td,J=8.4,2.6Hz,1H);13 C NMR(126MHz,Chloroform-d)δ207.6,166.2(d,J=2.7Hz),162.2(d,J=246.5Hz),133.2(d,J= 8.4Hz), 129.7 (d, J = 8.0Hz), 125.2 (d, J = 3.2Hz), 117.5 (d, J = 21.2Hz), 116.6 (d, J = 23.9Hz).

[0083] NMR data of the product from Example 25: 1 H NMR (500MHz, Chloroform-d) δ7.93 (s, 1H), 7.85 (d, J = 7.8Hz, 1H), 7.46 (d, J = 8.1Hz, 1H), 7.40 (t, J = 7.9Hz, 1H); 13 C NMR (126MHz, CDCl3) δ207.5,166.3,134.1,133.0,130.6,129.5,129.3,127.6.

[0084] NMR data of the product from Example 27: 1 H NMR (500MHz, Chloroform-d) δ8.22(s,1H),8.17(d,J=7.9Hz,1H),7.74(d,J=7.9Hz,1H),7.59(t,J=7.8Hz,1H); 13 C NMR (126MHz, CDCl3) δ207.4, 166.2, 132.6, 132.1, 130.7 (q, J = 32.9Hz), 128.6, 127.1 (q, J = 3.7Hz), 126.5 (q, J = 3.9Hz), 123.7 (q, J = 272.5Hz).

[0085] NMR data of the product from Example 29: 1 H NMR(500MHz,Chloroform-d)δ7.40–7.35(m,1H),7.33–7.24(m,3H),2.23(s,3H); 13 C NMR (126MHz, CDCl3) δ208.6,171.0,137.4,131.2,130.6,129.9,129.6,125.6,19.7.

[0086] NMR data of the product from Example 30: 1H NMR (500MHz, Chloroform-d) δ7.47–7.42(m,1H),7.31(dd,J=7.5,1.7Hz,1H),7.04(td,J=7.5,1.1Hz,1H),7.00(d,J=8.4Hz,1H),3.79(s,3H); 13 C NMR (126MHz, CDCl3) δ208.6,169.2,157.7,131.6,130.8,120.8,120.5,111.6,55.7.

[0087] NMR data of the product from Example 31: 1 H NMR(500MHz,Chloroform-d)δ7.74(d,J=7.8Hz,1H),7.70(d,J=10.0Hz,1H),7.47–7.38(m,1H),7.19(td,J=8.4,2.6Hz,1H); 13 C NMR(126MHz,Chloroform-d)δ207.6,166.2(d,J=2.7Hz),162.2(d,J=246.5Hz),133.2(d,J= 8.4Hz), 129.7 (d, J = 8.0Hz), 125.2 (d, J = 3.2Hz), 117.5 (d, J = 21.2Hz), 116.6 (d, J = 23.9Hz).

[0088] NMR data of the product from Example 32: 1 H NMR (500MHz, Chloroform-d) δ7.93 (s, 1H), 7.85 (d, J = 7.8Hz, 1H), 7.46 (d, J = 8.1Hz, 1H), 7.40 (t, J = 7.9Hz, 1H); 13 C NMR (126MHz, CDCl3) δ207.5,166.3,134.1,133.0,130.6,129.5,129.3,127.6.

[0089] NMR data of the product from Example 33: 1 H NMR(500MHz,Chloroform-d)δ7.67(d,J=8.2Hz,1H),7.45–7.39(m,1H),7.38–7.31(m,2H); 13 C NMR (126MHz, CDCl3) δ207.3,169.7,133.2,133.1,131.2,131.2,127.2,122.9.

[0090] NMR data of the product from Example 34: 1 H NMR(500MHz,Chloroform-d)δ7.69(dd,J=8.4,2.1Hz,1H),7.57(s,1H),6.93(d,J=8.5Hz,1H),3.94(s,3H),3.92(s,3H); 13 C NMR (126MHz, CDCl3) δ208.3,166.8,151.0,148.3,123.9,122.8,112.6,110.3,56.0,55.9.

[0091] NMR data of the product from Example 35: 1 H NMR(500MHz,Chloroform-d)δ7.94–7.85(m,1H),7.82–7.71(m,1H),7.29–7.16(m,1H); 13 C NMR(126MHz,Chloroform-d)δ207.3,165.1,151.7(dd,J=258.8,12.8Hz),149.7(dd,J=253.6,12.7 Hz), 128.1 (dd, J = 6.7, 4.0Hz), 126.3 (dd, J = 6.7, 3.7Hz), 118.9 (d, J = 19.6Hz), 117.1 (d, J = 17.7Hz).

[0092] NMR data of the product from Example 36: 1 H NMR(500MHz,Chloroform-d)δ8.10(d,J=2.1Hz,1H),7.85(dd,J=8.4,2.1Hz,1H),7.53(d,J=8.4Hz,1H); 13 C NMR (126MHz, CDCl3) δ207.2,165.1,135.0,132.5,131.3,131.1,130.1,128.6.

[0093] NMR data of the product from Example 37: 1 H NMR(500MHz,Chloroform-d)δ7.79(d,J=2.2Hz,1H),7.72(dd,J=8.3,2.2Hz,1H),7.41(d,J=8.3Hz,1H),2.42(s,3H); 13 C NMR (126MHz, CDCl3) δ207.9,166.9,136.9,136.1,131.8,129.8,128.8,128.1,20.1.

[0094] NMR data of the product from Example 38: 1 H NMR (500MHz, Chloroform-d) δ7.97(d,J=8.1Hz,1H),7.90(d,J=8.1Hz,1H),7.67–7.62(m,1H),7.64–7.59(m,1H),7.58–7.54(m,1H),7.53–7.46(m,2H); 13 C NMR (126MHz, CDCl3) δ208.8,169.9,133.7,131.6,130.5,128.7,128.6,128.4,126.8,126.3,124.8,124.8.

[0095] NMR data of the product from Example 40: 1 H NMR (500MHz, Chloroform-d) δ8.03 (d, J = 3.6Hz, 1H), 7.64 (s, 1H), 6.66–5.92 (m, 1H); 13 C NMR (126MHz, CDCl3) δ205.0,157.1,146.9,145.5,114.7,111.7.

[0096] NMR data of the product from Example 41: 1 H NMR (500MHz, Chloroform-d) δ8.34 (d, J = 3.8Hz, 1H), 7.51 (d, J = 5.1Hz, 1H), 7.14 (t, J = 4.4Hz, 1H); 13 C NMR (126MHz, CDCl3) δ205.6,161.3,133.8,131.6,130.7,127.1.

[0097] NMR data of the product from Example 42: 1 H NMR(500MHz,Chloroform-d)δ8.92–8.84(m,1H),7.81–7.73(m,1H),7.45–7.33(m,1H); 13 C NMR (126MHz, CDCl3) δ207.6,161.9,132.5,129.3,128.4,125.1.

[0098] NMR data of the product from Example 44: 1H NMR(500MHz,Chloroform-d)δ8.48(s,1H),7.71(d,J=7.8Hz,1H),7.59(d,J=8.4Hz,1H),7.47–7.38(m,1H),7.30(t,J=7.5Hz,1H); 13 C NMR (126MHz, CDCl3) δ205.2,157.2,155.2,147.8,127.6,127.2,123.7,123.0,111.5,110.9.

[0099] NMR data of the product from Example 49: 1 H NMR (500MHz, Chloroform-d) δ3.45–3.25(m,1H),1.98–1.92(m,2H),1.87–1.81(m,2H),1.76(d,J=14.5Hz,1H),1.51–1.36(m,4H),1.34–1.24(m,1H); 13 C NMR (126MHz, CDCl3) δ209.1,176.2,40.0,31.7,26.2,25.9.

[0100] Table 1-50 shows the conversion rates and products of the reactions.

[0101]

[0102]

[0103]

[0104] Based on the above-described preferred embodiments of the present invention, and through the foregoing description, those skilled in the art can make various changes and modifications without departing from the inventive concept. The technical scope of this invention is not limited to the contents of the specification, but must be determined according to the scope of the claims.

Claims

1. A synthetic method of 4-substituted-5H-1, 2, 3-dithiazole-5-thione, The synthetic method comprises the following steps: The synthetic method comprises the following steps: The synthetic method comprises the following steps: (I) adding methyl ketone compound, nitrogen-containing small molecule, elemental sulfur, catalyst, sulfoxide compound and organic solvent; (II) mixing the reactants thoroughly and heating the reaction; (III) purifying to obtain the product; The iodine-containing compound is selected from one or more of the following: elemental iodine, hydroiodic acid, potassium iodide, sodium iodide, ammonium iodide, iodine chloride, iodine bromide, iodine trichloride, N-iodosuccinimide, tetrabutylammonium iodide, hydroxyltoluenesulfonyl iodobenzene, [bis(trifluoroacetoxy)iodo]benzene, iodobenzenediacetic acid, trimethyl iodine sulf oxide; The sulfoxide compound is selected from one or more of the following: dimethyl sulfoxide, dibutyl sulfoxide, methyl phenyl sulfoxide, dibenzyl sulfoxide, diphenyl sulfoxide, tetramethylene sulfoxide; The nitrogen-containing small molecule is selected from one or more of the following: ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, ammonium sulfate, ammonium sulfite, ammonium bisulfate; ammonium carbonate; ammonium bicarbonate; ammonium nitrate; ammonium acetate; ammonium sulfide, ammonium thiocyanate, hydroxylamine hydrochloride, methoxyamine hydrochloride, phenylhydrazine, benzylamine, cyanamide, benzenesulfonylamine, formylhydrazine, benzhydrazine, benzene thioformylhydrazine, ethylenediamine, propylenediamine, diphenylamine, dibenzylamine, triethylamine, tripropylamine, tetrabutylammonium hydrogen sulfate, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium fluoride trihydrate, tetrabutylammonium hydroxide, tetrabutylammonium chloride, tetrabutylammonium acetate, tetramethylammonium iodide, tetramethoxyammonium chloride; The methyl ketone compound is selected from one or more of the following: acetophenone, p-methylacetophenone, p-ethylacetophenone, p-propylacetophenone, p-tert-butylacetophenone, p-pentylacetophenone, p-cyclohexylacetophenone, p-morpholinylacetophenone, p-methoxyacetophenone, p-methylthioacetophenone, p-hydroxyacetophenone, p-phenylacetophenone, p-trifluoromethylacetophenone, 4-acetylbenzoic acid methyl ester, p-fluoroacetophenone, p-chloroacetophenone, p-bromoacetophenone, p-iodoacetophenone, p-cyanoacetophenone, p-nitroacetophenone, m-methylacetophenone, m-methoxyacetophenone, m-fluoroacetophenone, m-chloroacetophenone, m-bromoacetophenone, m-trifluoromethylacetophenone, m-nitroacetophenone, o-methylacetophenone, o-methoxyacetophenone, o-fluoroacetophenone, o-chloroacetophenone, o-bromoacetophenone, 3, 4-dimethoxyacetophenone, 3, 4-difluoroacetophenone, 3, 4-dichloroacetophenone, 3-methyl-4-chloroacetophenone, 1-acetylnaphthalene, 2-acetylnaphthalene, 2-acetylfuran, 2-acetylthiophene, 3-acetylthiophene, 4-acetylpyridine, 2-acetylbenzofuran, 2-acetylbenzothiophene, 3-acetylphenanthrene, 2-pentanone, methyl tert-butyl ketone, acetyl cyclohexane, 1-acetyladamantane; The structure of the product is as follows: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 2. The method of synthesis of claim 1, wherein, The reaction atmosphere is: air atmosphere; the molar ratio of methyl ketone compound, nitrogen-containing small molecule, elemental sulfur, sulfoxide compound and catalyst is 1.0-10.0:2.0-30.0:4.0-40.0:3.0-40.0:0.2-5.0; at the same time, the reaction temperature is 125-140 DEG C; the reaction time is 2-24h; the organic solvent is one or more of 1, 4-dioxane and ethylene glycol dimethyl ether.

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