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

Abstract

The present invention belongs to the technical field of heterocyclic compound preparation, specifically 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, realizes the preparation of polysubstituted thiazole compounds under mild conditions and from easily available starting materials, and overcomes the technical defects of the prior art preparation method, such as the use of pre-functionalized substrates, transition metal catalysts, microwave radiation and multi-step reactions.

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:

[0006] The preparation method of 2,4,5-trisubstituted thiazole compounds comprises the following steps:

[0007] by and R 2 -NCS as raw material, NH 4 I is a catalyst, the raw material and the catalyst are mixed in a solvent, heated at 90°C to 120°C for 6h to 10h, and NH 4 I pair The isoxazole ring is opened and then reacted with R 2 -NCS ring closure method to obtain 2,4,5-trisubstituted thiazole compounds;

[0008] 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.

[0009] Preferably, the halogen is selected from F, Cl or Br.

[0010] 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.

[0011] Preferably, , R 2 -NCS and NH 4 The molar ratio of I is 1:1~2:0.1~1.

[0012] Preferably, , R 2 -NCS and NH 4 The molar ratio of I is 1:1:0.2; , R 2 -NCS and NH 4 The yield of I molar ratio of 1:1:0.2 is similar to that of 1:1:1, so NH 4 No need to use high amounts.

[0013] Preferably, the heating temperature is 100° C. and the heating time is 8 hours. This condition is the best reaction condition.

[0014] Compared with the prior art, the present invention has the following beneficial effects:

[0015] 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.

[0016] 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.

[0017] 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

[0018] Figure 1 This is a diagram of the preparation method of substituted thiazole compounds in the prior art.

[0019] Figure 2 The figure is a reaction type diagram for preparing heterocyclic structure compounds using isoxazole as raw material in the prior art.

[0020] Figure 3 This is the hydrogen spectrum of 4-phenyl-2-(anilino)thiazole-5-carboxamide of Example 1.

[0021] Figure 4 This is the carbon spectrum of 4-phenyl-2-(anilino)thiazole-5-carboxamide of Example 1.

[0022] Figure 5 This is a schematic diagram of the preparation principle of the 2,4,5-trisubstituted thiazole compounds of the present invention.

[0023] Figure 6 This is the hydrogen spectrum of 4-phenyl-2-(2-fluorophenyl)aminothiazole-5-carboxamide of Example 9.

[0024] Figure 7 This is the carbon spectrum of 4-phenyl-2-(2-fluorophenyl)aminothiazole-5-carboxamide of Example 9.

[0025] Figure 8 This is the fluorine spectrum of 4-phenyl-2-(2-fluorophenyl)aminothiazole-5-carboxamide of Example 9.

[0026] Fig. 9 This is the hydrogen spectrum of 4-phenyl-2-(2-chlorophenyl)aminothiazole-5-carboxamide of Example 10.

[0027] Fig.10 This is the carbon spectrum of 4-phenyl-2-(2-chlorophenyl)aminothiazole-5-carboxamide of Example 10.

[0028] Fig.11 This is the hydrogen spectrum of 4-phenyl-2-(2-bromophenyl)aminothiazole-5-carboxamide of Example 11. DETAILED DESCRIPTION

[0029] 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.

[0030] 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.

[0031] The present invention has certain influence on the type of catalyst, solvent, NH 4 The amount of I used, reaction atmosphere, reaction temperature and time were screened to obtain high yield of 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0032] The technical solution of the present invention is further explained by using embodiments and comparative examples, as shown below:

[0033] Example 1

[0034] The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide comprises the following steps:

[0035] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed together in tetrahydrofuran solvent, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I is 1:1:0.2; under nitrogen atmosphere, heated at 100°C for 8h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide; the hydrogen and carbon spectra are as shown Figure 3~Figure 4 As shown, 1 H NMR (400 MHz, DMSO- d 6 ) 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 N 3 OS,[M+H] + 296.0852. Found 296.0860.

[0036] The reaction equation is:

[0037] .

[0038] Example 2

[0039] 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:

[0040] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed in the solvent 1,4-dioxane, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4The molar ratio of I was 1:1:0.2; under a nitrogen atmosphere, the mixture was heated at 100°C for 8 h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0041] Example 3

[0042] 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:

[0043] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed together in tetrahydrofuran solvent, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I was 1:1:0.2; under a nitrogen atmosphere, the mixture was heated at 90°C for 8 h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0044] Example 4

[0045] 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:

[0046] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed together in tetrahydrofuran solvent, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I was 1:1:0.2; under a nitrogen atmosphere, the mixture was heated at 120°C for 8 h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0047] Example 5

[0048] 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:

[0049] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed together in tetrahydrofuran solvent, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I is 1:1:0.2; the mixture is heated at 100°C for 8 hours under air atmosphere to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0050] Example 6

[0051] 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:

[0052] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed together in tetrahydrofuran solvent, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I was 1:1:0.2; heated at 100°C for 6 h under a nitrogen atmosphere to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0053] Example 7

[0054] 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:

[0055] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed together in tetrahydrofuran solvent, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I is 1:1:0.2; under a nitrogen atmosphere, heating at 100°C for 10 h gives 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0056] Example 8

[0057] The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I is replaced by 1:1:0.2 to 1:1:1, comprising the steps of:

[0058] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed together in tetrahydrofuran solvent, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I was 1:1:1; under a nitrogen atmosphere, heated at 100°C for 8 h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0059] Example 9

[0060] The preparation method of 4-phenyl-2-(2-fluorophenyl)aminothiazole-5-carboxamide comprises the following steps:

[0061] 2-fluorophenyl isocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed together in the solvent tetrahydrofuran, 2-fluorophenyl isocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I is 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 as follows Figure 6~Figure 8 shown.

[0062] Example 10

[0063] The preparation method of 4-phenyl-2-(2-chlorophenyl)aminothiazole-5-carboxamide comprises the following steps:

[0064] 2-Chlorophenylisocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed together in the solvent tetrahydrofuran, 2-chlorophenyl isocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I is 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 and carbon spectra are as follows Figure 9~Figure 10 shown.

[0065] Embodiment 11

[0066] The preparation method of 4-phenyl-2-(2-bromophenyl)aminothiazole-5-carboxamide comprises the following steps:

[0067] 2-bromophenyl isocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed together in the solvent tetrahydrofuran, 2-bromophenyl isocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I is 1:1:0.2; heated at 100°C for 8h under nitrogen atmosphere to obtain 4-phenyl-2-(2-bromophenyl)aminothiazole-5-carboxamide. Fig.11 shown.

[0068] Comparative Example 1

[0069] The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that NH 4 I is replaced by an equimolar amount of NaI, comprising the following steps:

[0070] 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.

[0071] Comparative Example 2

[0072] The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that NH 4 I is replaced with an equimolar amount of KI, comprising the following steps:

[0073] 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.

[0074] Comparative Example 3

[0075] The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that NH 4 I is replaced with an equimolar amount of CuI, comprising the following steps:

[0076] 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.

[0077] Comparative Example 4

[0078] The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that NH 4 I was replaced by an equimolar amount n -Bu 4 NI, including the following steps:

[0079] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and a catalyst n -Bu 4 NI is mixed in tetrahydrofuran solvent, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst n -Bu 4The molar ratio of NI is 1:1:0.2; under a nitrogen atmosphere, heating at 100°C for 8 hours gives 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0080] Comparative Example 5

[0081] The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that NH 4 I was replaced by an equimolar amount of NH 4 C1, comprising the steps of:

[0082] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 Cl was mixed in tetrahydrofuran solvent, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of Cl is 1:1:0.2; under a nitrogen atmosphere, heating at 100°C for 8 hours gives 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0083] Comparative Example 6

[0084] The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that NH 4 I was replaced by an equimolar amount of NH 4 Br, comprising the following steps:

[0085] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 Br is mixed in tetrahydrofuran solvent, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of Br is 1:1:0.2; under a nitrogen atmosphere, heating at 100°C for 8 hours gives 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0086] Comparative Example 7

[0087] 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:

[0088] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed in the solvent methanol, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I was 1:1:0.2; under a nitrogen atmosphere, the mixture was heated at 100°C for 8 h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0089] Comparative Example 8

[0090] 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:

[0091] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed together in the solvent N,N-dimethylformamide, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I was 1:1:0.2; under a nitrogen atmosphere, the mixture was heated at 100°C for 8 h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0092] Comparative Example 9

[0093] 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:

[0094] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed together in the solvent dimethyl sulfoxide, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I was 1:1:0.2; under a nitrogen atmosphere, the mixture was heated at 100°C for 8 h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0095] Comparative Example 10

[0096] 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:

[0097] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed in deionized water, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I was 1:1:0.2; under a nitrogen atmosphere, the mixture was heated at 100°C for 8 h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0098] Comparative Example 11

[0099] 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:

[0100] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed together in the solvent dichloroethane, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I was 1:1:0.2; under a nitrogen atmosphere, the mixture was heated at 100°C for 8 h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0101] Comparative Example 12

[0102] 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:

[0103] Benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 I was mixed together in tetrahydrofuran solvent, benzene isothiocyanate, 3-phenylisoxazole-5-amine and catalyst NH 4 The molar ratio of I was 1:1:0.2; under a nitrogen atmosphere, the mixture was heated at 60°C for 8 h to obtain 4-phenyl-2-(anilino)thiazole-5-carboxamide.

[0104] Comparative Example 13

[0105] The preparation method of 4-phenyl-2-(anilino)thiazole-5-carboxamide is the same as the preparation steps of Example 1, except that NH 4 I reacts, comprising the steps of:

[0106] 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.

[0107] 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:

[0108] Table 1 Comparison of product yields of Example 1 to Example 8 and Comparative Example 1 to Comparative Example 13

[0109]

[0110] During the investigation of the conditions, the investigation and screening of iodized salt showed that NH 4 I is better than NaI, KI, CuI and n-Bu 4 The catalytic activity of NI is also better than that of other types of ammonium salts, such as NH4 Cl and NH 4 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 methanol and H 2 When tetrahydrofuran was replaced by a protic solvent such as N,N-dimethylformamide, dichloroethane and dimethyl sulfoxide, the yield dropped significantly or even failed to react. Further investigation of the reaction temperature showed that the yield was similar at 90°C to 120°C, but the yield dropped significantly when the temperature was lowered to 60°C. Finally, 100°C was determined to be the optimal reaction temperature. Fortunately, this reaction was 2 The atmosphere may contain O 2 The reaction was able to proceed with high yields in an air atmosphere, indicating that oxygen had no effect on the conversion. In addition, the reaction yield was not reduced within a reaction time of 6 h to 10 h. If the reaction was carried out without the catalysis of ammonium iodide, no product was detected.

[0111] 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 are independently selected from a benzene ring or an aryl group containing a substituent, and the substituent is selected from a halogen, a trifluoromethyl group or an alkyl group having 1 to 5 carbon atoms; The solvent is selected from tetrahydrofuran or 1,4-dioxane.

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: R 2 The molar ratio of -NCS to NH4I is 1:1~2:0.1~1.

4. The method for preparing 2,4,5-trisubstituted thiazole compounds according to claim 3, characterized in that: R 2 The molar ratio of -NCS to NH4I is 1:1:0.

2.

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

6. 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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