Preparation method and application of isothiazole-5(2H)-imine compounds

Abstract

The present invention provides a method for preparing an isothiazole-5(2H)-imine compound and its application. The method uses a thioacrylamide compound shown in formula I as a raw material, and a polysubstituted isothiazole-5(2H)-imine compound shown in formula II undergoes a ring-forming reaction under the action of an organic high-valent iodine compound. Compared with the preparation method of polysubstituted isothiazole-5(2H)-imine compounds in the prior art, the present invention utilizes an organic high-valent iodine compound to participate in the ring-forming reaction of the thioacrylamide compound, thereby realizing the preparation of polysubstituted isothiazole-5(2H)-imine compounds. The synthesis method has the advantages of easy availability of raw materials, mild reaction conditions, no safety risks, and no need to use a metal catalyst.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a preparation method of an isothiazole-5(2H)-imine compound and application thereof. Background Art

[0002] Isothiazole-5(2H)-imine compounds are a class of five-membered heterocyclic compounds that are widely found in natural products and synthetic compounds. Most of them have biological and pharmacological activities and can be used in many fields such as chemistry, biology, and medicine. It has been reported that they can be used as CB2 receptor modulators for the treatment of pain. They can also be used in the field of pesticides to effectively inhibit the life activities of insects.

[0003] There are two main methods for preparing isothiazole-5(2H)-imine compounds: (1) using 3-aminothioacrylamide derivatives to undergo a cyclization reaction under the action of trimethyloxonium tetrafluoroborate, liquid bromine or azodicarboxylic acid ester compounds. However, in this method, trimethyloxonium tetrafluoroborate is expensive, liquid bromine is highly toxic and corrosive, and azodicarboxylic acid ester compounds are prone to explosion, which poses a great safety hazard and greatly limits their application; (2) preparing them through the ring-opening and recyclization reaction of isothiazole mixtures, but this method requires the pre-synthesis of isothiazole precursors, and the synthesis route is long and the steps are complicated. Summary of the invention

[0004] In view of this, the object of the present invention is to provide a preparation method of isothiazole-5(2H)-imine compounds and their application. The method has readily available raw materials, mild reaction conditions, simple operation and is easy to implement.

[0005] To achieve this object, the present invention adopts the following technical solutions:

[0006] In a first aspect, the present invention provides a method for preparing an isothiazole-5(2H)-imine compound, comprising the following steps:

[0007] The thioacrylamide compound shown in formula I undergoes a cyclization reaction under the action of an organic high-valent iodine compound to obtain an isothiazole-5(2H)-imine compound shown in formula II;

[0008]

[0009] Among them, R 1 , R 2 , R 3 , R 4 are each independently selected from -A, -Ar or -Het;

[0010] The -A is selected from substituted or unsubstituted C1 to C 30An alkyl group or a substituted or unsubstituted C3-C7 cycloalkyl group;

[0011] The -Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl;

[0012] The -Het is selected from substituted or unsubstituted C5 to C 10 unsaturated monocyclic heterocyclic group or substituted or unsubstituted C5~C 10 The number of heteroatoms in the unsaturated monocyclic heterocyclic group and the unsaturated bicyclic heterocyclic group is independently selected from 1 to 4, and the heteroatoms are selected from any one or more of N, O or S.

[0013] The organic high-valent iodine compound is well known to those skilled in the art, wherein the valence state of iodine is trivalent or pentavalent.

[0014] Preferably, the -A is selected from substituted or unsubstituted C1 to C 10 or a substituted or unsubstituted C3-C7 cycloalkyl group.

[0015] Preferably, the -Het is selected from a substituted or unsubstituted C5-C7 unsaturated monocyclic heterocyclic group or a substituted or unsubstituted C8-C 12 An unsaturated bicyclic heterocyclic group.

[0016] Preferably, the -Ar is selected from substituted phenyl, substituted biphenyl or substituted naphthyl, and the substituents in the substituted phenyl, substituted biphenyl or substituted naphthyl are each independently selected from C1 to C 10 Any one or more of alkoxy, -A, -COA, -COOA, -CN or -NO2.

[0017] More preferably, the -A is selected from substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted C3-C7 cycloalkyl.

[0018] More preferably, the substituents in the substituted phenyl, substituted biphenyl or substituted naphthyl are independently selected from any one or more of C1-C5 alkoxy, -A, -COA, -COOA, -CN or -NO2.

[0019] Preferably, the organic hypervalent iodine compound is selected from any one or more of iodosobenzene, iodobenzene diacetate, iodobenzene di(trifluoroacetate), hydroxy-p-toluenesulfonyloxyiodobenzene, 2-iodosobenzoic acid, iodosobenzene or Dess-Martin periodinane reagent.

[0020] Preferably, the molar ratio of the thioacrylamide compound to the organic high-valent iodine compound is 1:(0.5-5).

[0021] Preferably, the reaction is carried out in the presence of an organic solvent, and the organic solvent is selected from any one or more of dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, ethanol, ether, acetonitrile, tetrahydrofuran, ethyl acetate or 1,4-dioxane.

[0022] Preferably, the reaction is carried out in the presence of an auxiliary agent, and the auxiliary agent is selected from any one or more of trifluoroacetic acid, boron trifluoride etherate, 2,2,2-trifluoroethanol, hexafluoroisopropanol, acetic acid, p-toluenesulfonic acid or elemental iodine.

[0023] Preferably, the molar ratio of the thioacrylamide compound to the auxiliary agent is 1:(0.5-4).

[0024] Preferably, the reaction temperature is 0 to 100° C. and the reaction time is 0.1 to 10 h.

[0025] In a second aspect, the present invention provides a drug, comprising the isothiazole-5(2H)-imine compound prepared by the above preparation method.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] The present invention provides a method for preparing isothiazole-5(2H)-imine compounds. Compared with the prior art, the present invention uses an organic high-valent iodine compound to activate the enamine group in the thioacrylamide compound, guides the thioacrylamide compound to undergo a ring-forming reaction, and thus realizes the synthesis of isothiazole-5(2H)-imine compounds. In the method, the organic high-valent iodine compound and the thioacrylamide compound are simple and easy to obtain as experimental raw materials, and the price is relatively cheaper. The conditions required for the reaction are mild, there is no safety risk, and no metal catalyst is required. In addition, the prepared isothiazole-5(2H)-imine compound can have multiple substituent groups, indicating that the preparation method has a wide range of applications. Through nuclear magnetic resonance spectroscopy analysis of hydrogen spectrum and carbon spectrum testing, it is found that the preparation method provided by the present invention can accurately synthesize the corresponding target product. DETAILED DESCRIPTION

[0028] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0029] All raw materials involved in the present invention have no particular limitation on their sources and can be purchased from the market or prepared by conventional techniques known to those skilled in the art.

[0030] In view of the problems that the preparation method of isothiazole-5(2H)-imine compounds in the prior art has high raw material cost, complex reaction and safety risks, the present invention provides a preparation method of isothiazole-5(2H)-imine compounds, comprising the following steps:

[0031] The thioacrylamide compound shown in formula I undergoes a cyclization reaction under the action of an organic high-valent iodine compound to obtain an isothiazole-5(2H)-imine compound shown in formula II;

[0032]

[0033] Among them, R 1 , R 2 , R 3 , R 4 are each independently selected from -A, -Ar or -Het;

[0034] The -A is selected from substituted or unsubstituted C1 to C 30 alkyl or substituted or unsubstituted C3-C7 cycloalkyl, preferably substituted or unsubstituted C1-C 20 alkyl or substituted or unsubstituted C3-C7 cycloalkyl, preferably substituted or unsubstituted C1-C 10 substituted or unsubstituted C3-C7 cycloalkyl, further preferably substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted C3-C7 cycloalkyl, most preferably substituted or unsubstituted C1-C3 alkyl or substituted or unsubstituted C3-C7 cycloalkyl. 30 The number of substituents in the alkyl group is preferably 1 to 20, more preferably 1 to 15, further preferably 1 to 10, further preferably 1 to 5, further preferably 1 to 3, and most preferably 1 to 2, and the substituents are preferably -Ar and / or -Het.

[0035] The -Het is selected from a substituted or unsubstituted C4-C7 unsaturated monocyclic heterocyclic group or a substituted or unsubstituted C7-C 12 An unsaturated bicyclic heterocyclic group, more preferably a substituted or unsubstituted C5-C7 unsaturated monocyclic heterocyclic group or a substituted or unsubstituted C8-C 12 An unsaturated bicyclic heterocyclic group, further preferably a substituted or unsubstituted C5-C6 unsaturated monocyclic heterocyclic group or a substituted or unsubstituted C9-C 12 The number of heteroatoms in the unsaturated monocyclic heterocyclic group and the unsaturated bicyclic heterocyclic group is independently selected from 1 to 4, and the heteroatoms are selected from any one or more of N, O or S. 10 unsaturated monocyclic heterocyclic group or substituted C7~C12 The number of substituents in the unsaturated bicyclic heterocyclic group is preferably 1 to 3, more preferably 1 or 2, and the substituents are preferably halogen, C1 to C 30 any one or more of -A, -COA, -COOA, -CN or -NO2, more preferably halogen, C1~C 20 One or more of -A, -COA, -COOA, -CN and -NO2, preferably halogen, C1~C 10 Any one or more of -A, -COA, -COOA, -CN or -NO2, further preferably any one or more of halogen, C1~C5 alkoxy, -A, -COA, -COOA, -CN or -NO2, most preferably any one or more of halogen, C1~C3 alkoxy, -A, -COA, -COOA, -CN or -NO2; the halogen is preferably any one or more of F, Cl, Br or I; the A is the same as the relevant contents of the above technical scheme, which will not be repeated here.

[0036] The -Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl; the number of substituents in the substituted phenyl, substituted biphenyl or substituted naphthyl is preferably 1 to 5, more preferably 1 to 3, and even more preferably 1 to 2; the position of the substituent in the substituted phenyl, substituted biphenyl or substituted naphthyl is preferably ortho and / or para; the substituent in the substituted phenyl, substituted biphenyl or substituted naphthyl is preferably halogen, C1 to C 30 any one or more of -A, -COA, -COOA, -CN or -NO2, more preferably halogen, C1~C 20 any one or more of -A, -COA, -COOA, -CN or -NO2, preferably halogen, C1~C 10 Any one or more of -A, -COA, -COOA, -CN or -NO2, further preferably any one or more of halogen, C1~C5 alkoxy, -A, -COA, -COOA, -CN or -NO2, most preferably any one or more of halogen, C1~C3 alkoxy, -A, -COA, -COOA, -CN or -NO2; the halogen is preferably one or more of -F, -Cl, -Br and -I; the A is the same as the relevant contents in the above technical scheme, which will not be repeated here.

[0037] In some embodiments of the present invention, the structural formulas of the thioacrylamide compound and the polysubstituted isothiazole-5(2H)-imine compound are shown in Formula I and Formula II, respectively, and the R1 , R 2 , R 3 Each independently is preferably selected from C1-C5 alkyl, phenyl or substituted phenyl, more preferably selected from C1-C3 alkyl, phenyl or substituted phenyl, wherein R 4 Preferably, the substituent is selected from phenyl or substituted phenyl. The substituent in the substituted phenyl is preferably any one or more of C1-C5 alkyl, C1-C5 alkoxy or -Cl, more preferably any one or more of C1-C3 alkyl, C1-C3 alkoxy or -Cl, and the number of the substituent is preferably 1 to 3, more preferably 1 to 2.

[0038] In some embodiments of the present invention, the structural formulas of the thioacrylamide compound and the polysubstituted isothiazole-5(2H)-imine compound are shown in Formula I and Formula II, respectively, and the R 1 , R 2 , R 3 Preferably, it is a C1-C5 chain alkyl group, wherein R 4 Preferably, it is phenyl or substituted phenyl. The substituent in the substituted phenyl is preferably any one or more of C1-C5 alkyl, C1-C5 alkoxy or -Cl. The number of substituents in the substituted phenyl is preferably 1-3.

[0039] In some embodiments of the present invention, the valence state of iodine in the organic hypervalent iodine compound is trivalent or pentavalent, and can be specifically selected from trivalent iodobenzoyl (PhIO), diacetate iodobenzene (PIDA), di(trifluoroacetic acid) iodobenzene (PIFA), hydroxy-p-toluenesulfonyloxyiodobenzene (HTIB) or pentavalent 2-iodobenzoic acid (IBX), iodobenzoyl (PhIO2) or Dess-Martin periodinane reagent (DMP) in any one or more, preferably any one or more of PhIO, PIDA, PIFA, IBX or DMP, and most preferably PIFA. According to research, if the amount of thioacrylamide compound added is too high, the reaction will be incomplete, and if it is too low, the organic hypervalent iodine compound will be wasted greatly. Therefore, the present invention preferably determines the molar ratio of thioacrylamide compound to organic hypervalent iodine compound to be 1: (0.5-5), more preferably 1: (0.5-3), more preferably 1: (1-2.5), and most preferably 1: (1.5-2). In some embodiments of the present invention, the molar ratio of the thioacrylamide compound to the organic high-valent iodine compound can be 1:1.2, 1:1.5, 1:2 or 1:3.

[0040] In some embodiments of the present invention, the thioacrylamide compound and the organic high-valent iodine compound are preferably reacted in the presence of an auxiliary agent, which can activate the organic high-valent iodine compound in advance, which is beneficial to the subsequent cyclization reaction of the thioacrylamide compound. Specifically, it can be selected from any one or more of trifluoroacetic acid, boron trifluoride etherate, 2,2,2-trifluoroethanol, hexafluoroisopropanol, acetic acid, p-toluenesulfonic acid or iodine. In some embodiments of the present invention, when the organic high-valent iodine compound is selected from PhIO, IBX or DMP, the addition of an auxiliary agent can further improve the yield of the reaction product.

[0041] In some embodiments of the present invention, the thioacrylamide compound, the organic hypervalent iodine compound and the optional auxiliary agent are preferably reacted in the presence of an organic solvent, and the organic solvent is soluble, and can be specifically selected from any one or more of dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, ethanol, ether, acetonitrile, tetrahydrofuran, ethyl acetate or 1,4-dioxane, preferably any one or more of dichloromethane, chloroform or 1,2-dichloroethane and other halogenated hydrocarbon solvents. In some embodiments of the present invention, it is preferred that the organic hypervalent iodine compound, the optional auxiliary agent and the organic solvent are first mixed, and the mixing is preferably carried out under stirring conditions so that the organic hypervalent iodine compound enters an activated state in advance, and then the thioacrylamide compound is added to react, wherein the concentration of the thioacrylamide compound in the reaction system is preferably 0.025 to 0.1 mmol / mL. The reaction temperature is preferably 0 to 100° C., more preferably 10 to 60° C., most preferably 15 to 35° C.; the reaction time is preferably 0.1 to 10 h, more preferably 0.5 to 6 h.

[0042] The above-mentioned “optional auxiliary agent” means that the auxiliary agent can be added to the reaction system according to actual needs, that is, it can be added or not.

[0043] In some embodiments of the present invention, after the reaction is completed, it is preferred that a post-purification treatment operation is further included. In the present invention, the obtained reaction solution is preferably poured into a saturated sodium chloride aqueous solution and then extracted with an organic solvent. The organic solvent can be specifically selected from any one or more of dichloromethane, chloroform, 1,2-dichloroethane, ether or ethyl acetate. After the extraction is completed, the extract is preferably dried, filtered, and the solvent is removed, and then the isothiazole-5 (2H) -imine compound shown in formula II is obtained by silica gel column chromatography. In some embodiments of the present invention, the drying is preferably carried out by anhydrous sodium sulfate to absorb the liquid in the extract, and the filtration and solvent removal are carried out according to conventional technical means well known to those skilled in the art. In some embodiments of the present invention, the eluent in the silica gel column chromatography is preferably a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is preferably (5-11): 1, more preferably (8-11): 1, and most preferably 10: 1.

[0044] The present invention utilizes an organic high-valent iodine compound to participate in the cyclization reaction of a thioacrylamide compound to synthesize an isothiazole-5(2H)-imine compound. The method has easy-to-obtain raw materials, simple operation, mild reaction conditions, and R 1 ~R 4 It can be a variety of different substituents and has a wide range of applications.

[0045] Through nuclear magnetic resonance spectroscopy analysis of hydrogen spectrum and nuclear magnetic resonance carbon spectrum testing, it is found that the preparation method provided by the present invention can accurately synthesize the corresponding isothiazole-5(2H)-imine compounds with a high yield. The isothiazole-5(2H)-imine compounds can be used to prepare drugs, which can relieve pain or inhibit insect activity.

[0046] In order to further illustrate the present invention, the following examples are provided for detailed description. The experimental raw materials used in the following examples of the present invention can be purchased from the market or prepared according to conventional preparation methods well known to those skilled in the art.

[0047] Wherein, the thioacrylamide compound represented by formula I is preferably prepared according to the synthesis method reported in the literature (ARKIVOC2009, (xii), 98);

[0048] The hydrogen and carbon spectra of all the compounds in the following examples were measured by a Bruker AV-300 nuclear magnetic resonance spectrometer; the mass spectrometry data were measured by a LTQ Orbitrap Velos Pro high-resolution mass spectrometer.

[0049] Example 1

[0050] This embodiment provides a 2,3-dimethyl-4-acetyl-N-phenylisothiazole-5(2H)-imine, and the preparation method thereof is as follows:

[0051] Under stirring at room temperature, add 1.5mmol of PIFA and 10.0mL of dichloromethane to a 50mL round-bottom flask and mix well, then add 1.0mmol of 2-acetyl-3-methylamino-N-phenylbut-2-enethioamide and react at room temperature for 2.0 hours. After the reaction is completed, 2,3-dimethyl-4-acetyl-N-phenylisothiazole-5(2H)-imine is obtained with a yield of 84% and a purity of >99%;

[0052] The 2,3-dimethyl-4-acetyl-N-phenylisothiazole-5(2H)-imine obtained in Example 1 was analyzed by nuclear magnetic resonance spectroscopy to obtain its hydrogen nuclear magnetic spectrum, and the results are as follows:

[0053] 1 H NMR (300MHz, CDCl3): δ2.55 (s, 3H), 2.69 (s, 3H), 3.26 (s, 3H), 6.98 (d, J = 7.5Hz, 2H), 7.08 (t, J = 7.5Hz, 1H), 7.35 (t, J = 7.5Hz, 2H).

[0054] Example 2

[0055] This embodiment provides a 2-benzyl-3-methyl-4-acetyl-N-phenylisothiazole-5(2H)-imine, and the preparation method thereof is as follows:

[0056] Under stirring at 50° C., 2.5 mmol of PIDA and 10.0 mL of ethyl acetate were added to a 50 mL round-bottom flask and mixed evenly, and then 1.0 mmol of 2-acetyl-3-(benzylamino)-N-phenylbut-2-enethioamide was added and reacted for 6.0 hours. After the reaction was completed, the reaction solution was poured into 50.0 mL of saturated NaCl aqueous solution, and then extracted three times with 20.0 mL of ethyl acetate, the organic phases were combined, 3.0 g of anhydrous sodium sulfate was added for drying, the solid was filtered out, and the organic solvent was removed. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate=8:1) to obtain 2-benzyl-3-methyl-4-acetyl-N-phenylisothiazole-5(2H)-imine, with a yield of 64% and a purity of>99%.

[0057] The 2-benzyl-3-methyl-4-acetyl-N-phenylisothiazole-5(2H)-imine obtained in Example 2 was analyzed by nuclear magnetic resonance spectroscopy to obtain its nuclear magnetic carbon spectrum, and the results are as follows:

[0058] 13C NMR (75MHz, CDCl3): δ15.7,32.0,51.7,114.8,120.1,124.4,127.0,128.7,129.2,129.9,134.4,164.8,195.8.

[0059] Example 3

[0060] This embodiment provides a 2,3-dimethyl-4-acetyl-N-(3-methylphenyl)isothiazole-5(2H)-imine, and the preparation method thereof is as follows:

[0061] Under stirring at room temperature, 5.0 mmol of PhIO, 7.5 mmol of acetic acid and 20.0 mL of dichloromethane were added to a 50 mL round-bottom flask and mixed evenly, and then 1.0 mmol of 2-acetyl-3-methylamino-N-(m-tolyl)but-2-enethioamide was added and reacted for 3.5 hours. After the reaction was completed, the reaction solution was poured into 50.0 mL of saturated NaCl aqueous solution, and then extracted three times with 20.0 mL of dichloromethane, the organic phases were combined, 3.0 g of anhydrous sodium sulfate was added for drying, the solid was filtered out, and the organic solvent was removed. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain 2,3-dimethyl-4-acetyl-N-(3-methylphenyl)isothiazole-5(2H)-imine, with a yield of 65% and a purity of >99%.

[0062] The 2,3-dimethyl-4-acetyl-N-(3-methylphenyl)isothiazole-5(2H)-imine obtained in Example 3 was analyzed by nuclear magnetic resonance spectroscopy to obtain its nuclear magnetic carbon spectrum, and the results are as follows:

[0063] 1 H NMR (300MHz, CDCl3): δ2.34(s,3H),2.57(s,3H),2.68(s,3H),3.28(s,3H),7. 80(d,J=7.5Hz,1H), 6.82(s,1H), 6.92(d,J=7.5Hz,1H), 7.24(t,J=7.5Hz,1H).

[0064] Example 4

[0065] This embodiment provides a 2,3-dimethyl-4-acetyl-N-(4-nitrophenyl)isothiazole-5(2H)-imine, and the preparation method thereof is as follows:

[0066] Under stirring at 75°C, 1.0 mmol of PIFA and 30.0 mL of 1,2-dichloroethane were added to a 50 mL round-bottom flask and mixed evenly, and then 1.0 mmol of 2-acetyl-3-(methylamino)-N-(4-nitrophenyl)but-2-enethioamide was added and reacted for 5.0 hours. After the reaction, the reaction solution was poured into 50.0 mL of saturated NaCl aqueous solution, and then extracted three times with 20.0 mL of 1,2-dichloroethane, the organic phases were combined, 3.0 g of anhydrous sodium sulfate was added for drying, the solid was filtered out, and the organic solvent was removed. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain 2,3-dimethyl-4-acetyl-N-(4-nitrophenyl)isothiazole-5(2H)-imine, with a yield of 69% and a purity of >99%.

[0067] The 2,3-dimethyl-4-acetyl-N-(4-nitrophenyl)isothiazole-5(2H)-imine obtained in Example 4 was analyzed by nuclear magnetic resonance spectroscopy to obtain its hydrogen nuclear magnetic spectrum, and the results are as follows:

[0068] 1 H NMR (300MHz, CDCl3): δ2.12 (s, 3H), 2.54 (s, 3H), 3.34 (s, 3H), 7.04 (d, J = 9.0 Hz, 2H), 8.16 (d, J = 9.0 Hz, 2H).

[0069] Example 5

[0070] This embodiment provides a 2,3-dimethyl-4-propionyl-N-phenylisothiazole-5(2H)-imine, and the preparation method thereof is as follows:

[0071] Under stirring at 30°C, 2.0 mmol of PIFA, 1.0 mmol of hexafluoroisopropanol and 30.0 mL of chloroform were added to a 50 mL round-bottom flask and mixed evenly, and then 1.0 mmol of 2-propionyl-3-(methylamino)-N-phenylbut-2-enethioamide was added and reacted for 4.5 hours. After the reaction was completed, the reaction solution was poured into 50.0 mL of saturated NaCl aqueous solution, and then extracted three times with 20.0 mL of dichloromethane, the organic phases were combined, 3.0 g of anhydrous sodium sulfate was added for drying, the solid was filtered out, and the organic solvent was removed. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain 2,3-dimethyl-4-propionyl-N-phenylisothiazole-5(2H)-imine, with a yield of 73% and a purity of >99%.

[0072] The 2,3-dimethyl-4-propionyl-N-phenylisothiazole-5(2H)-imine obtained in Example 5 was analyzed by nuclear magnetic resonance spectroscopy to obtain its mass spectrum data, and the results are as follows:

[0073] HRMS(ESI)calcd for C 14 H 17 N2OS[M+H] + Theoretical value: 261.1056, measured value: 261.1068.

[0074] Example 6

[0075] This embodiment provides a 2,3-dimethyl-4-acetyl-N-phenylisothiazole-5(2H)-imine, and the preparation method thereof is as follows:

[0076] Under stirring at 0°C, 1.5 mmol of IBX, 0.5 mmol of trifluoroacetic acid and 35.0 mL of dichloromethane were added to a 50 mL round-bottom flask and mixed evenly, and then 1.0 mmol of 2-acetyl-3-(methylamino)-N-phenylbut-2-enethioamide was added and reacted for 1.5 hours. After the reaction was completed, the reaction solution was poured into 50.0 mL of saturated NaCl aqueous solution, and then extracted three times with 20.0 mL of dichloromethane, the organic phases were combined, 3.0 g of anhydrous sodium sulfate was added for drying, the solid was filtered out, and the organic solvent was removed. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain 2,3-dimethyl-4-acetyl-N-phenylisothiazole-5(2H)-imine, with a yield of 78% and a purity of >99%.

[0077] Example 7

[0078] This embodiment provides a 2-methyl-3-phenyl-4-propionyl-N-phenylisothiazole-5(2H)-imine, and the preparation method thereof is as follows:

[0079] Under stirring at 35° C., 3.0 mmol of PIFA and 30.0 mL of ether were added to a 50 mL round-bottom flask and mixed evenly, and then 1.0 mmol of 2-acetyl-3-methylamino-3-phenyl-N-phenylthioacrylamide was added and reacted for 6.0 hours. After the reaction was completed, the reaction solution was poured into 50.0 mL of a saturated NaCl aqueous solution, and then extracted three times with 20.0 mL of ethyl acetate, the organic phases were combined, 3.0 g of anhydrous sodium sulfate was added and dried, the solid was filtered out, and the organic solvent was removed. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate=9:1) to obtain 2-methyl-3-phenyl-4-propionyl-N-phenylisothiazole-5(2H)-imine, with a yield of 51% and a purity of>99%.

[0080] The 2-methyl-3-phenyl-4-propionyl-N-phenylisothiazole-5(2H)-imine obtained in Example 7 was analyzed by nuclear magnetic resonance spectroscopy to obtain its mass spectrum data. The results are as follows:

[0081] HRMS(ESI)calcd for C 19 H 19 N2OS[M+H] + Theoretical value: 323.1213, measured value: 323.1223.

[0082] Example 8

[0083] This embodiment provides a 2,3-dimethyl-4-benzoyl-N-(4-methoxyphenyl)isothiazole-5(2H)-imine, and the preparation method thereof is as follows:

[0084] Under stirring at 25°C, 1.5 mmol of PIFA and 20.0 mL of acetonitrile were added to a 50 mL round-bottom flask and mixed evenly, and then 1.0 mmol of 2-benzoyl-3-(methylamino)-N-(4-methoxyphenyl)but-2-enethioamide was added and reacted for 3.5 hours. After the reaction, the reaction solution was poured into 50.0 mL of saturated NaCl aqueous solution, and then extracted three times with 20.0 mL of dichloromethane, the organic phases were combined, 3.0 g of anhydrous sodium sulfate was added for drying, the solid was filtered out, and the organic solvent was removed. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1) to obtain 2,3-dimethyl-4-benzoyl-N-(4-methoxyphenyl)isothiazole-5(2H)-imine, with a yield of 58% and a purity of >99%.

[0085] The 2,3-dimethyl-4-benzoyl-N-(4-methoxyphenyl)isothiazole-5(2H)-imine obtained in Example 8 was analyzed by nuclear magnetic resonance spectroscopy to obtain its mass spectrum data. The results are as follows:

[0086] HRMS(ESI)calcd for C 19 H 19 N2O2S[M+H] + Theoretical value: 339.1162, measured value: 339.1156.

[0087] Example 9

[0088] This embodiment provides a 2,3-dimethyl-4-acetyl-N-(4-methoxyphenyl)isothiazole-5(2H)-imine, and the preparation method thereof is as follows:

[0089] Under stirring at 25°C, 2.5 mmol of DMP, 2.5 mmol of 2,2,2-trifluoroethanol and 40.0 mL of dichloromethane were added to a 50 mL round-bottom flask and mixed evenly, and then 1.0 mmol of 2-acetyl-3-(methylamino)-N-phenylbut-2-enethioamide was added and reacted for 1.0 hour. After the reaction was completed, the reaction solution was poured into 50.0 mL of saturated NaCl aqueous solution, and then extracted three times with 20.0 mL of dichloromethane, the organic phases were combined, 3.0 g of anhydrous sodium sulfate was added for drying, the solid was filtered out, and the organic solvent was removed. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate=8:1) to obtain 2,3-dimethyl-4-acetyl-N-(4-methoxyphenyl)isothiazole-5(2H)-imine, with a yield of 64% and a purity of>99%.

[0090] The 2,3-dimethyl-4-acetyl-N-(4-methoxyphenyl)isothiazole-5(2H)-imine obtained in Example 9 was analyzed by nuclear magnetic resonance spectroscopy to obtain its hydrogen nuclear magnetic spectrum. The results are as follows:

[0091] 1 H NMR (300MHz, CDCl3): δ2.59 (s, 3H), 2.70 (s, 3H), 3.30 (s, 3H), 3.82 (s, 3H), 6.91 (d, J = 9.0Hz, 2H), 6.93 (d, J = 9.0Hz, 2H).

[0092] Example 10

[0093] This embodiment provides a 2,3-dimethyl-4-acetyl-N-(2-chlorophenyl)isothiazole-5(2H)-imine, and the preparation method thereof is as follows:

[0094] Under stirring at 15°C, 2.0 mmol of PhIO, 3.0 mmol of trifluoroacetic acid and 20.0 mL of 1,2-dichloroethane were added to a 50 mL round-bottom flask and mixed evenly, and then 1.0 mmol of N-(2-chlorophenyl)-2-acetyl-3-methylaminobut-2-enethioamide was added and reacted for 8.0 hours. After the reaction, the reaction solution was poured into 50.0 mL of saturated NaCl aqueous solution, and then extracted three times with 20.0 mL of dichloromethane, the organic phases were combined, 3.0 g of anhydrous sodium sulfate was added for drying, the solid was filtered out, and the organic solvent was removed. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain 2,3-dimethyl-4-acetyl-N-(2-chlorophenyl)isothiazole-5(2H)-imine, with a yield of 55% and a purity of >99%.

[0095] The 2,3-dimethyl-4-acetyl-N-(2-chlorophenyl)isothiazole-5(2H)-imine obtained in Example 10 was analyzed by nuclear magnetic resonance spectroscopy to obtain its hydrogen nuclear magnetic spectrum. The results are as follows:

[0096] 1 H NMR (300MHz, CDCl3): δ2.59 (s, 3H), 2.74 (s, 3H), 3.30 (s, 3H), 6.99-7.06 (m, 2H), 7.22 (dd, J1 = 7.8Hz, J2 = 1.2Hz, 1H), 7.45 (d, J = 7.8Hz, 1H).

[0097] Comparative Example 1

[0098] Under stirring at room temperature, 3.1 mmol of N-(4-nitrophenyl)-2-nitro-3,3-diphenylaminothioacrylamide was added to 6.2 mL of DMF to form a solution, to which 3.3 mmol of diethyl azodicarboxylate was added, and the reaction was carried out for 1.0 hour (monitored by TLC), and then poured into ice water, the precipitated yellow solid was filtered, washed with a large amount of water, and dried in a vacuum oven overnight to obtain 1.1 g of 2-phenyl-3-anilino-4-nitro-N-(4-nitrophenyl)isothiazole-5(2H)-imine, with a yield of 84%. (Helv.Chim.Acta, 1997, 80, 273.)

[0099] This method only explores the cyclization reaction of thioacrylamide with a nitro structure at the 2-position. The azodicarbonate compounds needed in the reaction are extremely prone to explosion and have certain safety hazards. During the raw material synthesis process, two alkylthio groups need to be removed to generate two molecules of thiol to synthesize one molecule of raw material N-(4-nitrophenyl)-2-nitro-3,3-diphenylaminothioacrylamide. The atom economy of the reaction is poor, and the thiol is highly toxic.

[0100] The above description of the disclosed embodiments enables those skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing an isothiazole-5(2H)-imine compound, characterized in that: The following steps are involved: The thioacrylamide compound shown in formula I undergoes a cyclization reaction under the action of an organic high-valent iodine compound to obtain an isothiazole-5(2H)-imine compound shown in formula II; Among them, R 1 , R 2 , R 3 , R 4 are each independently selected from -A, -Ar or -Het; The -A is selected from substituted or unsubstituted C1 to C 30 An alkyl group or a substituted or unsubstituted C3-C7 cycloalkyl group; The -Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl; The -Het is selected from substituted or unsubstituted C5 to C 10 unsaturated monocyclic heterocyclic group or substituted or unsubstituted C5~C 10 The number of heteroatoms in the unsaturated monocyclic heterocyclic group and the unsaturated bicyclic heterocyclic group is independently selected from 1 to 4, and the heteroatoms are selected from any one or more of N, O or S; The organic high-valent iodine compound is selected from any one or more of iodosobenzene, diacetate iodobenzene, di(trifluoroacetic acid)iodobenzene, hydroxy-p-toluenesulfonyloxyiodobenzene, 2-iodosobenzoic acid, iodosobenzene or Dess-Martin periodinane reagent; The reaction is carried out in the presence of an auxiliary agent; The auxiliary agent is selected from any one or more of trifluoroacetic acid, boron trifluoride etherate, 2,2,2-trifluoroethanol, hexafluoroisopropanol, acetic acid, p-toluenesulfonic acid or elemental iodine.

2. The preparation method according to claim 1, characterized in that: The -A is selected from substituted or unsubstituted C1 to C 10 An alkyl group or a substituted or unsubstituted C3-C7 cycloalkyl group; The -Het is selected from a substituted or unsubstituted C5-C7 unsaturated monocyclic heterocyclic group or a substituted or unsubstituted C8-C 12 An unsaturated bicyclic heterocyclic group; The -Ar is selected from substituted phenyl, substituted biphenyl or substituted naphthyl, and the substituents in the substituted phenyl, substituted biphenyl or substituted naphthyl are each independently selected from C1 to C 10 Any one or more of alkoxy, -A, -COA, -COOA, -CN or -NO2.

3. The preparation method according to claim 2, characterized in that: The -A is selected from substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted C3-C7 cycloalkyl; The substituents in the substituted phenyl, substituted biphenyl or substituted naphthyl are independently selected from any one or more of C1-C5 alkoxy, -A, -COA, -COOA, -CN or -NO2.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the thioacrylamide compound to the organic high-valent iodine compound is 1:(0.5-5).

5. The preparation method according to claim 1, characterized in that: The reaction is carried out in the presence of an organic solvent; The organic solvent is selected from any one or more of dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, ethanol, ether, acetonitrile, tetrahydrofuran, ethyl acetate or 1,4-dioxane.

6. The preparation method according to claim 1, characterized in that: The molar ratio of the thioacrylamide compound to the auxiliary agent is 1:(0.5-4).

7. The preparation method according to claim 1, characterized in that: The reaction temperature is 0-100°C and the reaction time is 0.1-10h.

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