Preparation method of polysubstituted imidazole derivative

Abstract

The invention discloses a preparation method of a polysubstituted imidazole derivative, aryl alpha-bromo-ketone and alkyl amidine hydrochloride are taken as substrates, a specific tandem catalyst is introduced to effectively reduce the activation energy of reaction, cyclization reaction of aryl alpha-bromo-ketone compound and alkyl amidine hydrochloride is realized under mild conditions, the reaction efficiency is improved, and the reaction yield is increased. Therefore, the yield of the polysubstituted imidazole derivative is improved, the method is suitable for various different aryl alpha-bromo-ketone and alkyl amidine hydrochloride substrates, and the yield of the polysubstituted imidazole derivative can reach 75% or above.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthetic chemistry, and more specifically, to a method for preparing a polysubstituted imidazole derivative. Background Art

[0002] As a widely used organic synthesis fragment, polysubstituted imidazole compounds are often used in the organic molecular skeletons of bioactive drug molecules, organic optoelectronic materials, and fine electronic chemicals. In recent years, due to their good film-forming properties on metal surfaces, they have important application value in the corrosion and high temperature protection of metal surfaces. By adjusting the electronic effect and steric effect of polysubstituted imidazole molecules according to different application scenarios, the performance of imidazole molecules can be adjusted significantly to adapt to different application systems.

[0003] In 2004, Scott E. Wolkenberg's team reported a method for synthesizing polysubstituted imidazole compounds using 1,2-diketone, aldehyde and ammonium acetate as raw materials and acetic acid as solvent under high temperature microwave assistance. However, this method is highly efficient but faces challenges such as difficult handling of acetic acid solvent, excessive ammonium acetate, and high energy consumption at high temperature (Org. Lett. 2004, 6, 1453-1456.). In 2014, Arsalan Mirjafari and his research team successfully used α-hydroxyketone, benzyl alcohol and ammonium acetate as key raw materials, and synthesized a series of polysubstituted imidazole compounds with diverse structures through microwave-assisted high temperature reaction in a specific ionic liquid environment. Although this reaction pathway shows the potential for efficient synthesis, its dependence on high temperature conditions and microwave assistance makes the reaction conditions relatively harsh, and puts forward high requirements on the stability and operation control of the reaction system (Environ. Chem. lett. 2014, 12, 177-183.). In 2020, Vineet Jeena reported an efficient, environmentally friendly and practical internal alkyne and primary alcohol oxidation method for the synthesis of polysubstituted imidazoles. This green synthesis method uses an acid-free and metal-free molecular iodine / dimethyl sulfoxide system to obtain a variety of substituted imidazoles in moderate to good yields. However, this method is only used for the synthesis of 2,4,5-triarylimidazoles, and the reaction temperature is as high as 130°C and the reaction time is as high as 24h (Tetrahedron, 2020, 76, 131028.).

[0004] The prior art discloses a method for preparing a polysubstituted imidazole compound in a surface treatment agent for copper or copper alloy and its application. The polysubstituted imidazole compound is prepared at low temperature using an aromatic α-halogenated ketone compound and a phenylacetamidine hydrochloride compound as raw materials in combination with sodium methoxide and potassium carbonate. However, the yield of the polysubstituted imidazole compound prepared by the method is low, and the yield of the synthesized non-conjugated polysubstituted imidazole is still far behind that of the conjugated imidazole, and the reaction conditions are relatively harsh. Therefore, it is of great research value to develop an efficient and simple synthetic route for synthesizing polysubstituted imidazole compounds. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the defects and shortcomings of the existing preparation methods of polysubstituted imidazole derivatives, namely, harsh conditions and low yields, and provide a preparation method of polysubstituted imidazole derivatives. The cyclization reaction of an aromatic α-bromo ketone compound and an alkyl amidine is analyzed and decomposed into two steps of a condensation reaction and a nucleophilic substitution reaction, and a catalyst suitable for a tandem reaction is introduced to activate the two reaction steps respectively. The preparation method of the present invention has simple and easy-to-control conditions, is suitable for synthesizing polysubstituted imidazole derivatives from a variety of aromatic α-bromo ketones and alkyl amidine hydrochloride substrates, and has a high yield.

[0006] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0007] A method for preparing a polysubstituted imidazole derivative comprises the following steps:

[0008] Fully reacting an aromatic α-bromo ketone compound, an alkyl amidine hydrochloride, an inorganic base, and a tandem reaction catalyst in an organic solvent system, and purifying after the reaction to obtain the polysubstituted imidazole compound;

[0009] The structural formula of the aromatic α-bromoketone compound is shown in formula (I), and the structural formula of the alkyl amidine hydrochloride is shown in formula (II):

[0010]

[0011] X1 and X2 can be independently selected from any one of hydrogen, fluorine and chlorine;

[0012] R can be selected from one of hydrogen, methyl, ethyl and propyl;

[0013] n is one of 0, 1, 2, and 3;

[0014] The tandem reaction catalyst includes a condensation catalyst and a nucleophilic substitution catalyst. First, the condensation catalyst catalyzes the dehydration condensation reaction of the carbon-oxygen double bond and the amino group, and then the nucleophilic substitution catalyst activates the bromine functional group and catalyzes the nucleophilic substitution reaction of the carbon-nitrogen double bond to bromine.

[0015] Reaction equation of the present invention is as follows:

[0016]

[0017] The present invention utilizes the concept of tandem catalytic reaction, takes aryl α-bromo ketone and alkyl amidine hydrochloride as substrates, introduces a specific tandem catalyst to realize the condensation reaction and nucleophilic substitution reaction steps in the reaction step by step, firstly introduces a Schiff base reaction catalyst to catalyze the dehydration condensation reaction of C=O double bond and amino group, and then introduces a nucleophilic reaction catalyst to activate the bromine functional group, catalyzing C=NH to perform nucleophilic substitution reaction on C-Br bond. The original single-step catalytic reaction is carried out step by step, and the catalytic activation energy of the two small reactions is reduced respectively, thereby reducing the total reaction activation energy, effectively promoting the efficient cyclization reaction, realizing the cyclization reaction of aryl α-bromo ketone compound and alkyl amidine hydrochloride under mild conditions, improving the reaction efficiency, and thus improving the yield of polysubstituted imidazole derivatives.

[0018] In order to further improve the preparation yield of the polysubstituted imidazole derivatives, preferably, n is 0 or 1 in the structural formula of the alkyl amidine hydrochloride.

[0019] In a specific embodiment, the molar ratio of the aromatic α-bromo ketone compound to the alkyl amidine hydrochloride of the present invention is 1:0.9 to 1:1.5, preferably 1:1.01.

[0020] In a specific embodiment, the molar ratio of the aromatic α-bromoketone compound to the condensation catalyst of the present invention is 1:0.01 to 0.1, preferably 1:0.05.

[0021] In a specific embodiment, the molar ratio of the aromatic α-bromoketone compound to the nucleophilic substitution catalyst of the present invention is 1:0.01 to 0.1, preferably 1:0.05.

[0022] In a specific embodiment, the condensation catalyst of the present invention can be any one of sodium iodate, calcium nitrate, scandium trifluoromethanesulfonate, acetic acid, trifluorosulfonate or piperidine, more preferably scandium trifluoromethanesulfonate and / or acetic acid.

[0023] In a specific embodiment, the nucleophilic substitution catalyst of the present invention can be any one of ammonium iodide, ammonium bromide, ammonium chloride, cuprous iodide, cuprous bromide, a mixture of cuprous chloride and silver hexafluoroantimonate, copper trifluoromethanesulfonate-oxazoline, disodium ethylenediaminetetraacetate-zinc bromide or disodium ethylenediaminetetraacetate-cuprous iodide, more preferably a mixture of cuprous chloride and silver hexafluoroantimonate.

[0024] In the mixture of cuprous chloride and silver hexafluoroantimonate, the molar ratio of cuprous chloride to silver hexafluoroantimonate is 1:0.5-2.5.

[0025] In a specific embodiment, the inorganic base of the present invention can be preferably any one of sodium hydroxide, potassium hydroxide, potassium carbonate, ammonium nitrate, sodium bicarbonate or cesium carbonate. The use of the above preferred inorganic bases can further improve the reaction activity and reduce the preparation cost.

[0026] In a specific embodiment, the organic solvent of the present invention can be selected from at least one of N,N-dimethylformamide, toluene, acetonitrile, chloroform, tetrahydrofuran, ethanol or water.

[0027] In a specific embodiment, the reaction temperature of the present invention is 80-100° C., preferably 80° C., and the reaction time is 5-10 h, preferably 8 h.

[0028] Preferably, X1 and X2 in the formula (I) can be independently selected from any one of hydrogen or chlorine groups, R can be selected from one of hydrogen, methyl and ethyl, and the aromatic α-bromo ketone compound can be, for example, a compound of the following structure:

[0029]

[0030] The preparation method of the present invention can be used for the synthesis of various polysubstituted imidazoles, and the substrate has strong applicability, for example:

[0031] Synthesis of 2-(2,4-dichlorobenzyl)-4-phenyl-1H-imidazole, the specific reaction process is as follows:

[0032]

[0033] Synthesis of 2-(2,4-dichlorobenzyl)-4-(2,4-dichlorophenyl)-5-methyl-1H-imidazole, the specific reaction process is as follows:

[0034]

[0035] Synthesis of 2-(2,4-dichlorophenethyl)-4-(2,4-dichlorophenyl)-5-methyl-1H-imidazole, the specific reaction process is as follows:

[0036]

[0037] Synthesis of 2-(2,4-dichlorophenyl)-5-methyl-4-phenyl-1H-imidazole, the specific reaction process is as follows:

[0038]

[0039] Synthesis of 4-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole, the specific reaction process is as follows:

[0040]

[0041] Synthesis of 2,4-bis(2,4-dichlorophenyl)-5-ethyl-1H-imidazole, the specific reaction process is as follows:

[0042]

[0043] In a specific embodiment, in order to further purify the product, the purification treatment after the reaction in the preparation method of the polysubstituted imidazole derivative of the present invention may include filtration, washing, decolorization, concentration and recrystallization, filtration, secondary recrystallization and other steps to obtain a purified polysubstituted imidazole derivative. Among them, the two filtrations can remove the remaining catalyst, the decolorization treatment can adsorb insoluble impurities, the solvent in the concentration and recrystallization and secondary recrystallization steps can be recovered by distillation, and the condensation catalyst and nucleophilic substitution catalyst in the reaction process can also be reused, which can effectively save production costs.

[0044] In a specific embodiment, the solvent for recrystallization of the present invention can be any one of methanol, chloroform or ethyl acetate.

[0045] In a specific embodiment, the decolorizing agent used in the decolorizing treatment of the present invention is activated carbon, preferably powdered activated carbon with a particle size of 200 to 300 meshes.

[0046] In a specific embodiment, preferably, the mass ratio of the aromatic α-bromoketone compound to the activated carbon is 100:1 to 250:1, and more preferably the mass ratio of the aromatic α-bromoketone compound to the activated carbon is 200:1.

[0047] Compared with the prior art, the present invention has the following beneficial effects:

[0048] The preparation method of the polysubstituted imidazole derivatives of the present invention adopts a tandem catalysis mode, which reduces the activation energy of the reaction, so that the reaction can be completed efficiently under mild conditions, and is applicable to a variety of different aromatic α-bromoketones and alkyl amidine hydrochloride substrates. The yield of the polysubstituted imidazole derivatives can reach more than 75%, and the purity can reach more than 97%. DETAILED DESCRIPTION

[0049] The present invention is further described below in conjunction with specific embodiments, but the embodiments do not limit the present invention in any form. Unless otherwise specified, the raw materials and reagents used in the embodiments of the present invention are conventionally purchased raw materials and reagents.

[0050] The mixture of cuprous chloride and silver hexafluoroantimonate (CuCl / AgSbF6) used in the embodiments of the present invention is compounded in a molar ratio of cuprous chloride to silver hexafluoroantimonate of 1:1.

[0051] Example 1

[0052] A method for preparing 2-(2,4-dichlorobenzyl)-4-phenyl-1H-imidazole comprises the following steps:

[0053]

[0054] S1. Weigh 24.0g of 2-(2,4-dichlorophenyl)acetamidine hydrochloride and 8.0g of sodium hydroxide into a 500mL four-necked flask, add 100mL of acetonitrile, stir thoroughly, add 2.46g of catalyst scandium trifluoromethanesulfonate (Sc(OTf)3) and 2.20g of catalyst CuCl / AgSbF6,

[0055] Weigh 19.7 g of 2'-bromoacetophenone and dissolve it in 50 mL of acetonitrile in a constant pressure dropping funnel, and slowly add it dropwise to the four-necked flask. After the addition is complete, raise the reaction temperature to 80°C and react for 8 hours. Monitor the reaction progress by TLC. When 2'-bromoacetophenone is completely consumed, the system temperature drops to room temperature.

[0056] S2. The reaction is then purified by filtering, washing with water, adding 0.5 g of activated carbon, stirring and dissolving for 30 minutes for decolorization, filtering the activated carbon, concentrating and recrystallizing, filtering, and re-crystallizing from ethyl acetate to obtain 2-(2,4-dichlorobenzyl)-4-phenyl-1H-imidazole.

[0057] Wherein, the molar ratio of the aromatic α-bromoketone compound to the alkyl amidine hydrochloride is 1:1.01;

[0058] The molar ratio of the aromatic α-bromoketone compound to the condensation catalyst scandium trifluoromethanesulfonate is 1:0.05;

[0059] The molar ratio of the aromatic α-bromo ketone compound to the mixture of the nucleophilic substitution catalyst cuprous chloride and silver hexafluoroantimonate is 1:0.05.

[0060] The calculated yield was 85% and the purity was 97%.

[0061] The results of related products were characterized by H NMR spectroscopy.

[0062] 1 H NMR(500MHz,Chloroform-d)δ7.85-7.83(m,2H),7.76-7.75(m,1H),7.50-7.47(m,2 H),7.42-7.41(m,2H),7.36-7.34(m,1H),7.23(dd,J=8.2,2.2Hz,1H),4.24(s,2H).

[0063] Example 2

[0064] A method for preparing 2-(2,4-dichlorobenzyl)-4-(2,4-dichlorophenyl)-5-methyl-1H-imidazole comprises the following steps:

[0065]

[0066] S1. Weigh 24.0g of 2-(2,4-dichlorophenyl)acetamidine hydrochloride and 8.0g of sodium hydroxide into a 500mL four-necked flask, add 100mL of acetonitrile. After thorough stirring, add 32.46g of the catalyst scandium trifluoromethanesulfonate Sc(OTf) and 2.20g of the catalyst CuCl / AgSbF6.

[0067] Weigh 28.0 g of 2'-bromo-2,4-dichloropropiophenone and dissolve it in 50 mL of acetonitrile in a constant pressure dropping funnel, and slowly add it dropwise to a four-necked flask. After the addition is complete, raise the reaction temperature to 80°C and react for 8 hours. Monitor the reaction progress by TLC. When 2'-bromo-2,4-dichloropropiophenone is completely consumed, the system temperature drops to room temperature.

[0068] S2. The reaction was then purified by filtering, washing with water, and 0.5 g of activated carbon was stirred and dissolved for 30 minutes for decolorization. The activated carbon was filtered, concentrated and recrystallized, filtered, and recrystallized twice with ethyl acetate to obtain 2-(2,4-dichlorobenzyl)-4-(2,4-dichlorophenyl)-5-methyl-1H-imidazole.

[0069] Wherein, the molar ratio of the aromatic α-bromoketone compound to the alkyl amidine hydrochloride is 1:1.01;

[0070] The molar ratio of the aromatic α-bromoketone compound to the condensation catalyst scandium trifluoromethanesulfonate is 1:0.05;

[0071] The molar ratio of the aromatic α-bromo ketone compound to the mixture of the nucleophilic substitution catalyst cuprous chloride and silver hexafluoroantimonate is 1:0.05.

[0072] The yield was calculated to be 80% and the purity was 97%.

[0073] The results of related products were characterized by H NMR spectroscopy.

[0074] 1 H NMR(500MHz,Chloroform-d)δ7.62(d,J=2.3Hz,1H),7.54-7.52(d,J=9.0Hz,1H),7 .44-7.41(m,2H),7.36-7.34(m,1H),7.24-7.22(m,1H),4.19(s,2H),2.42(s,3H).

[0075] Example 3

[0076] A method for preparing 4-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole comprises the following steps:

[0077]

[0078] S1. Weigh 22.6g of 2,4-dichlorobenzamide hydrochloride and 8.0g of sodium hydroxide into a 500mL four-necked flask, add 100mL of acetonitrile, stir thoroughly, add 0.30g of catalyst acetic acid CH3COOH and 2.20g of catalyst CuCl / AgSbF6,

[0079] Weigh 24.6g of 2'-bromo-4-chloropropiophenone and dissolve it in 50mL of acetonitrile in a constant pressure dropping funnel, slowly drop it into the four-necked flask, raise the reaction temperature to 80℃ and react for 8h. Monitor the reaction progress by TLC. When 2'-bromo-4-chloropropiophenone is completely consumed, the system temperature drops to room temperature.

[0080] S2. The reaction was then purified by filtering, washing with water, stirring and dissolving 0.5 g of activated carbon for 30 min, filtering the activated carbon, concentrating and recrystallizing, filtering, and re-recrystallizing with ethyl acetate to obtain 4-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole.

[0081] Wherein, the molar ratio of the aromatic α-bromoketone compound to the alkyl amidine hydrochloride is 1:1.01;

[0082] The molar ratio of the aromatic α-bromoketone compound to the condensation catalyst acetic acid is 1:0.05;

[0083] The molar ratio of the aromatic α-bromo ketone compound to the mixture of the nucleophilic substitution catalyst cuprous chloride and silver hexafluoroantimonate is 1:0.05.

[0084] The calculated yield was 86% and the purity was 97%.

[0085] The results of related products were characterized by H NMR spectroscopy. 1 H NMR (500MHz, Chloroform-d) δ7.80 (d, J=9.0Hz, 1H), 7.62-7.60 (m, 3H), 7.47-7.45 (m, 3H), 2.48 (s, 3H).

[0086] Example 4

[0087] A method for preparing 2-(2,4-dichlorophenethyl)-4-(2,4-dichlorophenyl)-5-methyl-1H-imidazole comprises the following steps:

[0088]

[0089] S1. Weigh 25.5g of 3-(2,4-dichlorophenyl)propionamide amidine hydrochloride and 8.0g of sodium hydroxide into a 500mL four-necked flask, add 100mL of acetonitrile. After thorough stirring, add 0.30g of catalyst acetic acid CH3COOH and 2.20g of catalyst CuCl / AgSbF6.

[0090] Weigh 28.0 g of 2'-bromo-2,4-dichloropropiophenone and dissolve it in 50 mL of acetonitrile in a constant pressure dropping funnel, and slowly add it dropwise to a four-necked flask. After the addition is complete, raise the reaction temperature to 80°C and react for 8 hours. Monitor the reaction progress by TLC. When 2'-bromo-2,4-dichloropropiophenone is completely consumed, the system temperature drops to room temperature.

[0091] S2. The reaction was then purified by filtering, washing with water, stirring and dissolving 0.5 g of activated carbon for 30 min, filtering the activated carbon, concentrating and recrystallizing, filtering, and secondary recrystallization with ethyl acetate to obtain 2-(2,4-dichlorophenethyl)-4-(2,4-dichlorophenyl)-5-methyl-1H-imidazole.

[0092] Wherein, the molar ratio of the aromatic α-bromoketone compound to the alkyl amidine hydrochloride is 1:1.01;

[0093] The molar ratio of the aromatic α-bromoketone compound to the condensation catalyst acetic acid is 1:0.05;

[0094] The molar ratio of the aromatic α-bromo ketone compound to the mixture of the nucleophilic substitution catalyst cuprous chloride and silver hexafluoroantimonate is 1:0.05.

[0095] The calculated yield was 75% and the purity was 97%.

[0096] The results of related products were characterized by H NMR spectroscopy.

[0097] 1 H NMR(500MHz,Chloroform-d)δ7.62(d,J=2.3Hz,1H),7.53(d,J=9.0Hz,1H),7.44-7.42(m,1H) ,7.34(d,J=2.0Hz,1H),7.27-7.25(m,1H),7.21-7.19(m,1H),3.00-2.95(m,4H),2.42(s,3H).

[0098] Example 5

[0099] A method for preparing 2-(2,4-dichlorophenyl)-4-(4-fluorophenyl)-5-methyl-1H-imidazole comprises the following steps:

[0100]

[0101] S1. Weigh 22.6g of 2,4-dichlorobenzamide hydrochloride and 8.0g of sodium hydroxide into a 500mL four-necked flask, add 100mL of acetonitrile. After thorough stirring, add 0.30g of catalyst acetic acid CH3COOH and 2.20g of catalyst CuCl / AgSbF6.

[0102] Weigh 23.1g of 2'-bromo-4-fluoropropiophenone and dissolve it in 50mL of acetonitrile in a constant pressure dropping funnel, slowly drop it into a four-necked flask, raise the reaction temperature to 80°C and react for 8h. Monitor the reaction progress by TLC, and when 2'-bromo-4-fluoropropiophenone is completely consumed, the system temperature drops to room temperature;

[0103] S2. The reaction is then purified by filtering, washing with water, adding 0.5 g of activated carbon, stirring and dissolving for 30 minutes, filtering the activated carbon, concentrating and recrystallizing, filtering, and re-crystallizing with ethyl acetate to obtain a 2,4,5-trisubstituted imidazole compound.

[0104] The calculated yield was 87% and the purity was 97%.

[0105] The results of related products were characterized by H NMR spectroscopy.

[0106] 1 H NMR (500MHz, Chloroform-d) δ7.80 (d, J = 9.0 Hz, 2H), 7.61 (s, 1H), 7.46 (dd, J = 9.0, 2.2 Hz, 2H), 7.14 (t, J = 8.3 Hz, 3H), 2.48 (s, 3H).

[0107] Example 6

[0108] A method for preparing 2-(2,4-dichlorobenzyl)-4-(3,5-dichlorophenyl)-5-methyl-1H-imidazole comprises the following steps:

[0109]

[0110] S1.24.0g 2-(2,4-dichlorophenyl)acetamidine hydrochloride and 8.0g sodium hydroxide were placed in a 500mL four-necked flask, and 100mL acetonitrile was added. After thorough stirring, 0.30g acetic acid CH3COOH and 2.20g CuCl / AgSbF6 were added as catalysts.

[0111] Weigh 28.2 g of 2'-bromo-3,5-dichloropropiophenone and dissolve it in 50 mL of acetonitrile in a constant pressure dropping funnel, slowly drop it into the four-necked flask, raise the reaction temperature to 80°C and react for 8 hours after the addition is complete. Monitor the reaction progress by TLC, and when 2'-bromo-3,5-dichloropropiophenone is completely consumed, the system temperature drops to room temperature.

[0112] S2. The reaction is then purified by filtering, washing with water, adding 0.5 g of activated carbon, stirring and dissolving for 30 minutes, filtering the activated carbon, concentrating and recrystallizing, filtering, and re-crystallizing with ethyl acetate to obtain a 2,4,5-trisubstituted imidazole compound.

[0113] The yield was calculated to be 80% and the purity was 97%.

[0114] The results of related products were characterized by H NMR spectroscopy.

[0115] 1 H NMR(500MHz,Chloroform-d)δ7.48(d,J=2.2Hz,2H),7.41(dd,J=3.5,2.1Hz,2H),7.35( dt,J=8.2,1.0Hz,1H),7.23(dd,J=8.2,2.2Hz,1H),4.18(d,J=1.1Hz,2H),2.42(s,3H).

[0116] Example 7

[0117] A method for preparing 2-(2,4-dichlorophenethyl)-4-(2,4-dichlorophenyl)-5-methyl-1H-imidazole comprises the following steps:

[0118]

[0119] S1. Weigh 25.5g of 3-(2,4-dichlorophenyl)propionamide amidine hydrochloride and 8.0g of sodium hydroxide into a 500mL four-necked flask, add 100mL of acetonitrile, stir thoroughly, add 0.30g of catalyst acetic acid CH3COOH and 0.72g of catalyst ammonium iodide NH4I,

[0120] Weigh 28.0 g of 2'-bromo-2,4-dichloropropiophenone and dissolve it in 50 mL of acetonitrile in a constant pressure dropping funnel, and slowly add it dropwise to a four-necked flask. After the addition is complete, raise the reaction temperature to 80°C and react for 8 hours. Monitor the reaction progress by TLC. When 2'-bromo-2,4-dichloropropiophenone is completely consumed, the system temperature drops to room temperature.

[0121] S2. The reaction was then purified by filtering, washing with water, stirring and dissolving 0.5 g of activated carbon for 30 min, filtering the activated carbon, concentrating and recrystallizing, filtering, and secondary recrystallization with ethyl acetate to obtain 2-(2,4-dichlorophenethyl)-4-(2,4-dichlorophenyl)-5-methyl-1H-imidazole.

[0122] Wherein, the molar ratio of the aromatic α-bromoketone compound to the alkyl amidine hydrochloride is 1:1.01;

[0123] The molar ratio of the aromatic α-bromoketone compound to the condensation catalyst acetic acid is 1:0.05;

[0124] The molar ratio of the aromatic α-bromo ketone compound to the nucleophilic substitution catalyst ammonium iodide is 1:0.05.

[0125] The yield was calculated to be 70% and the purity was 97%.

[0126] The results of related products were characterized by H NMR spectroscopy.

[0127] 1 H NMR(500MHz,Chloroform-d)δ7.62(d,J=2.3Hz,1H),7.53(d,J=9.0Hz,1H),7.44-7.41(m,1H) ,7.33(d,J=2.0Hz,1H),7.27-7.26(m,1H),7.21-7.19(m,1H),3.00-2.96(m,4H),2.42(s,3H).

[0128] Comparative Example 1

[0129] A method for preparing 2-(2,4-dichlorobenzyl)-4-phenyl-1H-imidazole, which uses a one-step reaction method to carry out a cyclization reaction of an aromatic α-bromo ketone compound and an alkyl amidine, comprising the following steps:

[0130]

[0131] S1. Weigh 24.0g of 2-(2,4-dichlorophenyl)acetamidine hydrochloride and 8.0g of sodium hydroxide into a 500mL four-necked flask, add 100mL of acetonitrile and stir thoroughly.

[0132] Weigh 19.7 g of 2'-bromoacetophenone and dissolve it in 50 mL of acetonitrile in a constant pressure dropping funnel, slowly add it dropwise to the four-necked flask, raise the reaction temperature to 100 °C and react for 10 h, monitor the reaction progress by TLC, and when 2'-bromoacetophenone is completely consumed, the system temperature drops to room temperature;

[0133] S2. The reaction is then purified by filtering, washing with water, adding 0.5 g of activated carbon, stirring and dissolving for 30 minutes for decolorization, filtering the activated carbon, concentrating and recrystallizing, filtering, and performing secondary recrystallization with ethyl acetate multiple times to obtain 2-(2,4-dichlorobenzyl)-4-phenyl-1H-imidazole.

[0134] The molar ratio of the aromatic α-bromo ketone compound to the alkyl amidine hydrochloride is 1:1.01.

[0135] The calculated yield was 27% and the purity was 97%.

[0136] The results of related products were characterized by H NMR spectroscopy.

[0137] 1 H NMR(500MHz,Chloroform-d)δ7.85-7.83(m,2H),7.76-7.75(m,1H),7.50-7.47(m,2 H),7.42-7.41(m,2H),7.36-7.34(m,1H),7.23(dd,J=8.2,2.2Hz,1H),4.24(s,2H).

[0138] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the embodiments here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for preparing a polysubstituted imidazole derivative, characterized in that: The steps include: Fully reacting an aromatic α-bromo ketone compound, an alkyl amidine hydrochloride, an inorganic base, and a tandem reaction catalyst in an organic solvent system, and purifying after the reaction to obtain the polysubstituted imidazole compound; Wherein, the structural formula of the aromatic α-bromo ketone compound is shown in formula (I), and the structural formula of the alkyl amidine hydrochloride is shown in formula (II): X1 and X2 can be independently selected from any one of hydrogen, fluorine and chlorine; R can be selected from any one of hydrogen, methyl, ethyl, and propyl; n is one of 0, 1, 2, and 3; The tandem reaction catalyst includes a condensation catalyst and a nucleophilic substitution catalyst. First, the condensation catalyst catalyzes the dehydration condensation reaction of the carbon-oxygen double bond and the amino group, and then the nucleophilic substitution catalyst activates the bromine functional group and catalyzes the nucleophilic substitution reaction of the carbon-nitrogen double bond to bromine.

2. The method for preparing a polysubstituted imidazole derivative according to claim 1, characterized in that: n is 0 or 1.

3. The method for preparing a polysubstituted imidazole derivative according to claim 1, characterized in that: The molar ratio of the aromatic α-bromo ketone compound to the alkyl amidine hydrochloride is 1:0.9-1.

5.

4. The method for preparing a polysubstituted imidazole derivative according to claim 1, characterized in that: The molar ratio of the aromatic α-bromoketone compound to the condensation catalyst is 1:0.01-0.

1.

5. The method for preparing a polysubstituted imidazole derivative according to claim 1, characterized in that: The molar ratio of the aromatic α-bromoketone compound to the nucleophilic substitution catalyst is 1:0.01-0.

1.

6. The method for preparing a polysubstituted imidazole derivative according to claim 1, characterized in that: The condensation catalyst is any one of sodium iodate, calcium nitrate, scandium trifluoromethanesulfonate, acetic acid, trifluorosulfonate or piperidine.

7. The method for preparing a polysubstituted imidazole derivative according to claim 6, characterized in that: The condensation catalyst is scandium trifluoromethanesulfonate and / or acetic acid.

8. The method for preparing a polysubstituted imidazole derivative according to claim 1, characterized in that: The nucleophilic substitution catalyst is any one of ammonium iodide, ammonium bromide, ammonium chloride, cuprous iodide, cuprous bromide, a mixture of cuprous chloride and silver hexafluoroantimonate, copper trifluoromethanesulfonate-oxazoline, disodium ethylenediaminetetraacetate-zinc bromide or disodium ethylenediaminetetraacetate-cuprous iodide.

9. The method for preparing a polysubstituted imidazole derivative according to claim 8, characterized in that: The nucleophilic substitution catalyst is a mixture of cuprous chloride and silver hexafluoroantimonate.

10. The method for preparing a polysubstituted imidazole derivative according to claim 1, characterized in that: The reaction temperature is 80-100° C. and the reaction time is 5-10 hours.

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