Preparation method of 2, 4, 5-trisubstituted thiazole compound

Abstract

The invention belongs to the technical field of heterocyclic compound preparation, and particularly relates to a preparation method of a 2, 4, 5-trisubstituted thiazole compound. According to the invention, ammonium iodide is used as a catalyst, an isothiocyanic acid compound and an isoxazole-5-amine compound are used as raw materials, and ring opening / ring closing reaction is carried out under the catalytic action of ammonium iodide to obtain the 2, 4, 5-trisubstituted thiazole compound. According to the method, ammonium iodide is adopted as a catalyst, the polysubstituted thiazole compound is prepared from an easily available starting material under a mild condition, and the technical defects that a pre-functionalized substrate and a transition metal catalyst are used, and microwave radiation and multi-step reaction are needed in a preparation method in the prior art are overcome.

Description

Technical Field

[0001] The invention belongs to the technical field of heterocyclic compound preparation, and specifically relates to a method for preparing 2,4,5-trisubstituted thiazole compounds. Background Art

[0002] Thiazole compounds are an important class of heterocyclic building blocks that are widely found in bioactive molecules and natural products. In recent years, thiazole derivatives, especially 2,4,5-trisubstituted thiazole cores, have been extensively studied because of their various medicinal functions, including anti-inflammatory, anticancer, antiviral, antipsychotic, antibacterial and antifungal effects. So far, marketed drugs containing thiazole groups have achieved great success, such as thiothiazide, fentanyl, dasatinib and dabrafenib.

[0003] Considering the wide diversity of the thiazole skeleton, a lot of effort has been devoted to constructing structurally diverse thiazole compounds, including: (a) some traditional synthetic methods, such as the Hantzig synthesis, the Gabriel synthesis, and the Cook–Heilben synthesis, e.g. Figure 1 As shown in step a; (b) acid or base promotes the cyclization of N-propargylamine or substituted propargyl alcohol with thioamine, such as Figure 1 As shown in step b; (c) Huang, Jiao and Miura et al. used transition metals, such as iron, rhodium and copper, to synthesize substituted thiazoles by breaking CC bonds or CH bonds, such as Figure 1 As shown in step c; (d) constructing a multi-component tandem cyclization method under metal-free reaction conditions to construct a multi-substituted thiazole, such as Figure 1 Although these strategies have been demonstrated to be effective methods for the synthesis of polysubstituted thiazoles, they have the disadvantages of using prefunctionalized substrates, transition metal catalysts, requiring microwave irradiation, and multi-step reactions. Summary of the invention

[0004] In view of the deficiencies of the above-mentioned prior art, the purpose of the present invention is to provide a method for preparing 2,4,5-trisubstituted thiazole compounds. The present invention uses ammonium iodide as a catalyst, an isothiocyanate compound and an isoxazole-5-amine compound as raw materials, and performs a ring opening / re-ring closing reaction under the catalytic action of ammonium iodide to obtain 2,4,5-trisubstituted thiazole compounds. The present invention uses ammonium iodide as a catalyst to achieve the preparation of polysubstituted thiazole compounds under mild conditions and from easily available starting materials, overcoming the technical defects of the prior art preparation methods of using pre-functionalized substrates, transition metal catalysts, microwave radiation and multi-step reactions.

[0005] The present invention is achieved through the following technical solutions: The preparation method of 2,4,5-trisubstituted thiazole compounds comprises the following steps: by and R 2 -NCS is used as raw material, NH4I is used as catalyst, the raw material and catalyst are mixed in a solvent, heated at 90℃~120℃ for 6h~10h, and NH4I is used to The isoxazole ring is opened and then reacted with R 2 -NCS ring closure method to obtain 2,4,5-trisubstituted thiazole compounds; Among them, R 1 and R 2 They are independently selected from a benzene ring or an aryl group containing a substituent, and the substituent is selected from a halogen, an ester group, a trifluoromethyl group or an alkyl group having 1 to 5 carbon atoms.

[0006] Preferably, the halogen is selected from F, Cl or Br.

[0007] Preferably, the solvent is selected from tetrahydrofuran or 1,4-dioxane. Further, the solvent is selected from tetrahydrofuran. Studies have shown that the yield of 2,4,5-trisubstituted thiazole compounds prepared using tetrahydrofuran as solvent is the highest.

[0008] Preferably, , R 2 -The molar ratio of NCS to NH4I is 1:1~2:0.1~1.

[0009] Preferably, , R 2 -The molar ratio of NCS to NH4I is 1:1:0.2; , R 2 The yield of the molar ratio of -NCS to NH4I of 1:1:0.2 is similar to that of the molar ratio of 1:1:1, so NH4I does not need to be used in high amounts.

[0010] Preferably, the heating temperature is 100° C. and the heating time is 8 h. This condition is the optimal reaction condition.

[0011] Compared with the prior art, the present invention has the following beneficial effects: 1. The present invention uses ammonium iodide as a catalyst, an isothiocyanate compound and an isoxazole-5-amine compound as raw materials, and performs a ring opening / re-ring closing reaction under the catalytic action of ammonium iodide to obtain a 2,4,5-trisubstituted thiazole compound. The reaction principle of the present invention is: using ammonium iodide to open the isoxazole ring of the isoxazole-5-amine compound, and then closing the ring with the isothiocyanate compound to construct a 2,4,5-trisubstituted thiazole compound with different substituents.

[0012] Compared with the preparation method of substituted thiazole compounds in the prior art, the present invention uses cheap ammonium iodide as a catalyst to construct 2,4,5-trisubstituted thiazole compounds in a one-step series connection manner. The method of the present invention is efficient and easy to operate.

[0013] 2. As a useful three-atom structural unit, isoxazole has been widely used in various catalytic transformations to produce a variety of useful heterocyclic compounds. Figure 2 As shown, (1) the ring expansion reaction of isoxazole with vinyl diazoacetate or dimethyl sulfoxide constructs pyridine or pyrazine compounds; (2) the ring contraction reaction of isoxazole by iron catalysis or photocatalytic isomerization constructs aziridine compounds; (3) the cyclization reaction of alkynes and isoxazole catalyzed by transition metals constructs pyrrole ring compounds; (4) the reductive ring opening reaction promoted by metal reagents or catalysts. However, due to the relatively weak nucleophilicity of isoxazole, it is conventionally believed that isoxazole is difficult to react with thiocyanate. In the present invention, the present invention uses ammonium iodide as a catalyst and an isoxazole-5-amine compound as a raw material to achieve the ring opening / re-ring closing reaction of isothiocyanic acid compounds and isoxazole-5-amine compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is a diagram of the preparation method of substituted thiazole compounds in the prior art.

[0015] Figure 2 The figure is a reaction type diagram for preparing heterocyclic structure compounds using isoxazole as raw material in the prior art.

[0016] Figure 3 This is the hydrogen spectrum of 4-phenyl-2-(anilino)thiazole-5-carboxamide of Example 1.

[0017] Figure 4 This is the carbon spectrum of 4-phenyl-2-(anilino)thiazole-5-carboxamide of Example 1.

[0018] Figure 5 This is a schematic diagram of the preparation principle of the 2,4,5-trisubstituted thiazole compounds of the present invention.

[0019] Figure 6 This is the hydrogen spectrum of 4-phenyl-2-(2-fluorophenyl)aminothiazole-5-carboxamide of Example 9.

[0020] Figure 7 This is the carbon spectrum of 4-phenyl-2-(2-fluorophenyl)aminothiazole-5-carboxamide of Example 9.

[0021] Figure 8 This is the fluorine spectrum of 4-phenyl-2-(2-fluorophenyl)aminothiazole-5-carboxamide of Example 9.

[0022] Fig. 9This is the hydrogen spectrum of 4-phenyl-2-(2-chlorophenyl)aminothiazole-5-carboxamide of Example 10.

[0023] Fig.10 This is the carbon spectrum of 4-phenyl-2-(2-chlorophenyl)aminothiazole-5-carboxamide of Example 10.

[0024] Fig.11 This is the hydrogen spectrum of 4-phenyl-2-(2-bromophenyl)aminothiazole-5-carboxamide of Example 11. DETAILED DESCRIPTION

[0025] The specific embodiments of the present invention are described in detail below, but it should be understood that the protection scope of the present invention is not limited by the specific embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work belong to the protection scope of the present invention. The experimental methods described in the embodiments of the present invention are conventional methods unless otherwise specified.

[0026] Taking into account the shortcomings of the prior art preparation methods of substituted thiazole compounds, namely, the use of pre-functionalized substrates, transition metal catalysts, the need for microwave radiation and multi-step reactions, the present invention provides a novel preparation method of 2,4,5-trisubstituted thiazole compounds; in the present invention, ammonium iodide is used as a catalyst, an isothiocyanate compound and an isoxazole-5-amine compound are used as raw materials, and a ring-opening / re-ring-closing reaction is carried out under the catalytic action of ammonium iodide to obtain 2,4,5-trisubstituted thiazole compounds.

[0027] The present invention screens the catalyst type, solvent type, the amount of NH4I used, reaction atmosphere, reaction temperature and time to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide with a high yield.

[0028] The technical solution of the present invention is further explained by using embodiments and comparative examples, as shown below: Example 1 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I are mixed in tetrahydrofuran solvent, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I is 1:1:0.2; under nitrogen atmosphere, heat at 100°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide; hydrogen spectrum and carbon spectrum are shown as Figure 3~Figure 4 As shown, 1 H NMR (400 MHz, DMSO- d6) δ 10.48 (s, 1H), 7.76 – 7.68 (m, 2H), 7.64 (d, J = 8.0 Hz,2H), 7.47 – 7.38 (m, 3H), 7.34 (t, J = 7.6 Hz, 2H), 6.99 (t, J = 7.2 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 163.5, 162.5, 151.2, 141.0, 135.0, 129.5, 129.4,128.9, 128.6, 122.4, 117.8, 116.7. HRMS(ESI+): Calculated for C 16 H 13 N3OS, [M+H] + 296.0852. Found 296.0860.

[0029] The reaction equation is: .

[0030] Example 2 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that the solvent tetrahydrofuran is replaced by 1,4-dioxane, and comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I are mixed together in a solvent 1,4-dioxane, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I is 1:1:0.2; under a nitrogen atmosphere, heat at 100°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0031] Example 3 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that the heating temperature is replaced from 100° C. to 90° C., and comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I are mixed together in solvent tetrahydrofuran, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I is 1:1:0.2; under nitrogen atmosphere, heat at 90°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0032] Example 4 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that the heating temperature is replaced from 100° C. to 120° C., and comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I are mixed together in solvent tetrahydrofuran, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I is 1:1:0.2; under nitrogen atmosphere, heat at 120°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0033] Example 5 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that the nitrogen atmosphere is replaced by an air atmosphere, and comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I are mixed together in solvent tetrahydrofuran, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I is 1:1:0.2; under air atmosphere, heat at 100°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0034] Example 6 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that the reaction time is shortened from 8 h to 6 h, and comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I are mixed together in solvent tetrahydrofuran, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I is 1:1:0.2; under nitrogen atmosphere, heat at 100°C for 6h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0035] Example 7 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that the reaction time is extended from 8 h to 10 h, and comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I are mixed together in a solvent tetrahydrofuran, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I is 1:1:0.2; under a nitrogen atmosphere, heat at 100°C for 10 hours to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0036] Example 8 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I is replaced from 1:1:0.2 to 1:1:1, comprising the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I are mixed together in solvent tetrahydrofuran, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I is 1:1:1; under nitrogen atmosphere, heat at 100°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0037] Example 9 The preparation method of 4-phenyl-2-(2-fluorophenyl)aminothiazole-5-carboxamide comprises the following steps: 2-Fluorophenyl isocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I were mixed in tetrahydrofuran solvent, the molar ratio of 2-fluorophenyl isocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I was 1:1:0.2; heated at 100°C for 8h under nitrogen atmosphere to obtain 4-phenyl-2-(2-fluorophenyl)aminothiazole-5-carboxamide. The hydrogen spectrum, carbon spectrum and fluorine spectrum are shown in Figure 6~Figure 8 shown.

[0038] Example 10 The preparation method of 4-phenyl-2-(2-chlorophenyl)aminothiazole-5-carboxamide comprises the following steps: 2-Chlorophenyl isocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I were mixed in tetrahydrofuran solvent, the molar ratio of 2-chlorophenyl isocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I was 1:1:0.2; heated at 100°C for 8h under nitrogen atmosphere to obtain 4-phenyl-2-(2-chlorophenyl)aminothiazole-5-carboxamide. The hydrogen spectrum and carbon spectrum are shown in Figure 9~Figure 10 shown.

[0039] Embodiment 11 The preparation method of 4-phenyl-2-(2-bromophenyl)aminothiazole-5-carboxamide comprises the following steps: 2-bromophenyl isocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I were mixed in tetrahydrofuran solvent, the molar ratio of 2-bromophenyl isocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I was 1:1:0.2; heated at 100°C for 8h under nitrogen atmosphere to obtain 4-phenyl-2-(2-bromophenyl)aminothiazole-5-carboxamide. The hydrogen spectrum is shown in Fig.11 shown.

[0040] Comparative Example 1 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that NH4I is replaced by an equimolar amount of NaI, and comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NaI are mixed together in a solvent tetrahydrofuran, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NaI is 1:1:0.2; under a nitrogen atmosphere, heat at 100°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0041] Comparative Example 2 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that NH4I is replaced by an equal molar amount of KI, comprising the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst KI are mixed together in a solvent tetrahydrofuran, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst KI is 1:1:0.2; under a nitrogen atmosphere, heat at 100°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0042] Comparative Example 3 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that NH4I is replaced by an equimolar amount of CuI, and comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst CuI are mixed together in a solvent tetrahydrofuran, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst CuI is 1:1:0.2; under a nitrogen atmosphere, heat at 100°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0043] Comparative Example 4 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that NH4I is replaced by an equimolar amount of n -Bu4NI, comprising the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and a catalyst n -Bu4NI is mixed in the solvent tetrahydrofuran, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst n -Bu4NI has a molar ratio of 1:1:0.2; heated at 100°C for 8 h under a nitrogen atmosphere to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0044] Comparative Example 5 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that NH4I is replaced by an equal molar amount of NH4Cl, and comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4Cl are mixed together in solvent tetrahydrofuran, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4Cl is 1:1:0.2; under nitrogen atmosphere, heat at 100°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0045] Comparative Example 6 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that NH4I is replaced by an equal molar amount of NH4Br, comprising the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4Br are mixed together in solvent tetrahydrofuran, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4Br is 1:1:0.2; under nitrogen atmosphere, heat at 100°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0046] Comparative Example 7 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that the solvent tetrahydrofuran is replaced by methanol, and comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I are mixed together in solvent methanol, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I is 1:1:0.2; under nitrogen atmosphere, heat at 100°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0047] Comparative Example 8 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that the solvent tetrahydrofuran is replaced by N,N-dimethylformamide, and comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I are mixed together in solvent N,N-dimethylformamide, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I is 1:1:0.2; under nitrogen atmosphere, heat at 100°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0048] Comparative Example 9 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that the solvent tetrahydrofuran is replaced by dimethyl sulfoxide, and comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I are mixed together in a solvent dimethyl sulfoxide, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I is 1:1:0.2; under a nitrogen atmosphere, heat at 100°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0049] Comparative Example 10 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that the solvent tetrahydrofuran is replaced by deionized water, and comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I are mixed together in deionized water as a solvent, wherein the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I is 1:1:0.2; the mixture is heated at 100°C for 8 hours under a nitrogen atmosphere to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0050] Comparative Example 11 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that the solvent tetrahydrofuran is replaced by dichloroethane, and comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I are mixed together in solvent dichloroethane, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I is 1:1:0.2; under nitrogen atmosphere, heat at 100°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0051] Comparative Example 12 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that the heating temperature is replaced from 100° C. to 60° C., and comprises the following steps: Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I are mixed together in solvent tetrahydrofuran, and the molar ratio of benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH4I is 1:1:0.2; under nitrogen atmosphere, heat at 60°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0052] Comparative Example 13 The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that NH4I is not used for the reaction, and comprises the following steps: Benzene isothiocyanate and 3-phenylisoxazole-5-amine are mixed together in a solvent tetrahydrofuran, and the molar ratio of benzene isothiocyanate to 3-phenylisoxazole-5-amine is 1:1; under a nitrogen atmosphere, heat at 100°C for 8 hours to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0053] The following uses the products of Examples 1 to 8 of the present invention and Comparative Examples 1 to 13 as examples to study and compare the yields. The specific results are shown in Table 1: Table 1 Comparison of product yields of Example 1 to Example 8 and Comparative Example 1 to Comparative Example 13

[0054] During the condition investigation, the investigation and screening of iodine-containing salts showed that NH4I was superior to the catalysis of NaI, KI, CuI and n-Bu4NI, and was also superior to other types of ammonium salts, such as NH4Cl and NH4Br. The effect of solvent on the reaction of the present invention was also studied. The results showed that the reaction had similar effects when 1,4-dioxane and tetrahydrofuran were used as solvents. The desired product could be obtained with a yield of 80% when 1,4-dioxane was used as solvent. However, when tetrahydrofuran was replaced by protic solvents such as methanol and H2O or non-protic polar solvents such as N,N-dimethylformamide, dichloroethane and dimethyl sulfoxide, the yield decreased significantly, or even no reaction occurred. The reaction temperature was further investigated. The yield was similar at 90℃~120℃, but the yield decreased significantly when the temperature was reduced to 60℃. Finally, 100℃ was determined to be the optimal reaction temperature. Fortunately, this reaction can be carried out with high yield in N2 atmosphere or air atmosphere containing O2, indicating that oxygen has no effect on the conversion. In addition, the reaction yield is not reduced within the reaction time of 6h~10h. If the reaction is carried out without the catalysis of ammonium iodide, no product is detected.

[0055] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, they are also intended to be included.

Claims

1. A method for preparing a 2,4,5-trisubstituted thiazole compound, characterized in that: The steps include: by and R 2 -NCS is used as raw material, NH4I is used as catalyst, the raw material and catalyst are mixed in a solvent, heated at 90℃~120℃ for 6h~10h, and NH4I is used to The isoxazole ring is opened and then reacted with R 2 -NCS ring closure method to obtain 2,4,5-trisubstituted thiazole compounds; Among them, R 1 and R 2 They are independently selected from a benzene ring or an aryl group containing a substituent, and the substituent is selected from a halogen, an ester group, a trifluoromethyl group or an alkyl group having 1 to 5 carbon atoms.

2. The method for preparing 2,4,5-trisubstituted thiazole compounds according to claim 1, characterized in that: The halogen is selected from F, Cl or Br.

3. The method for preparing 2,4,5-trisubstituted thiazole compounds according to claim 1, characterized in that: The solvent is selected from tetrahydrofuran or 1,4-dioxane.

4. The method for preparing 2,4,5-trisubstituted thiazole compounds according to claim 1, characterized in that: , R 2 -The molar ratio of NCS to NH4I is 1:1~2:0.1~1.

5. The method for preparing 2,4,5-trisubstituted thiazole compounds according to claim 4, characterized in that: , R 2 The molar ratio of -NCS to NH4I is 1:1:0.

2.

6. The method for preparing 2,4,5-trisubstituted thiazole compounds according to claim 1, characterized in that: The heating temperature is 100°C.

7. The method for preparing 2,4,5-trisubstituted thiazole compounds according to claim 1, characterized in that: The heating time is 8h.

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