CN104844518A - Preparation method of 2,4,5-trisubstituted imidazole compound - Google Patents

Abstract

The present invention provides a method for preparing 2,4,5-trisubstituted imidazole compounds. A 2, 4,5-trisubstituted imidazoles. The synthesis method has the advantages of mild conditions, high yield and cheap and easy-to-obtain raw materials, which provides a simple and feasible method for efficiently synthesizing 2,4,5-trisubstituted imidazoles. The preparation method provided by the invention has reasonable design, readily available raw materials, simple and convenient operation, mild synthesis method conditions and high yield.

Description

A kind of preparation method of 2,4,5-trisubstituted imidazole compound

technical field

The invention belongs to a compound synthesis method, and mainly relates to a preparation method of 2,4,5-trisubstituted imidazole compounds.

Background technique

As a class of five-membered aromatic heterocyclic compounds, imidazoles are widely used in many fields such as medicine, pesticides, materials, and fine chemicals. Multi-substituted imidazoles, especially 2,4,5-trisubstituted imidazoles, are a very important class of imidazoles. Plays a crucial role in the synthesis of inflammatory drugs.

Since 2,4,5-trisubstituted imidazole compounds have very important application value, their synthesis methods have always been a hot spot in the field of synthesis. In recent years, new methods have emerged one after another, among which the following are representative.

(1) Microwave-assisted synthesis of polysubstituted imidazoles proposed by Scott E. Wolkenberg et al. (Scott E. Wolkenberg, David D. Wisnoski, William H. Leister, Org. Lett., 2004, 6, 1453-1456).

Formula 1, Scott E. Wolkenberg microwave-assisted synthesis of 2,4,5-trisubstituted imidazoles

This method uses difficult-to-prepare 1,2-diketones, aldehydes, and ammonium acetate as raw materials, and is synthesized by a microwave-assisted method under high temperature conditions, which is not suitable for large-scale mass production.

(2) Arsalan Mirjafari et al. used α-hydroxy ketones, benzyl alcohol and ammonium acetate as raw materials, and used microwave reactions in ionic liquids to finally obtain a series of 2,4,5-trisubstituted imidazole compounds (Arsalan Mirjafari, Environ Chem Lett (2014) 12:177-183).

Formula 2, Arsalan Mirjafari2,4,5-trisubstituted imidazole synthesis method

This reaction also requires microwave-assisted reaction under high temperature conditions, and the conditions are relatively harsh.

(3) Shubhanjan Mitra et al. synthesized 2,4,5-trisubstituted imidazoles in one pot under heating conditions using α-nitroolefins and amidines as raw materials and using nano-In ₂ O ₃ as a reaction catalyst (Shubhanjan Mitra, Avik Kumar Bagdi, Adinath Majee, Alakananda Hajra. Tetrahedron Lett. 2013, 54, 4982-4985).

Formula 3, Shubhanjan Mitra2,4,5-trisubstituted imidazole synthesis method

This method uses expensive nanometer In ₂ O ₃ as a catalyst, and the reaction needs a higher temperature to occur.

Although there are many reports on the synthesis of 2,4,5-trisubstituted imidazoles, the known synthetic methods still have problems such as difficult access to raw materials, use of highly toxic catalysts, low product yields, and poor applicability to different functional groups. , the above factors make it imperative to develop a novel preparation method for 2,4,5-trisubstituted imidazoles.

Contents of the invention

The technical problem to be solved in the present invention is to provide a preparation method of 2,4,5-trisubstituted imidazoles, by reacting α-nitroepoxides with amidines and bases in one pot at room temperature , that is, 2,3-disubstituted-2-nitrooxirane compounds, which are easy to be chemically synthesized, react with amidine compounds at room temperature.

Formula IV: General structural formula of 2,4,5-trisubstituted imidazole compounds

The preparation method of a 2,4,5-trisubstituted imidazole compound provided by the present invention is to stir the amidine compound II and base III in the corresponding solvent for 1 hour, and then add α-nitroepoxide I. Carry out ring closure reaction for 3-12 hours (preferably 8 hours), so as to obtain 2,4,5-trisubstituted imidazole compound IV. The alkali used is sodium methoxide. The reaction temperature was room temperature 25°C. Used solvent selects polar solvent or nonpolar solvent for use, and described polar solvent selects methanol, ethanol, n-propanol, n-butanol, isopropanol, tert-butanol, isobutanol, n-pentanol, ethylene glycol Or acetonitrile; non-polar solvents choose ether or carbon tetrachloride. Usually methanol. The obtained target product was purified by silica gel column chromatography (dichloromethane/methanol as eluent).

The specific steps of the preparation method of the present invention are as follows:

(1) Carry out cyclization reaction of α-nitroepoxide I, amidine compound II and base II (such as sodium methoxide) at 25°C for a reaction time of 3-12 hours, wherein α-nitroepoxide The molar ratio of the amidine compound to the base is 1:1.5:3;

(2) After the reaction solution obtained in step (1) was extracted with chloroform, the obtained organic layer (located in the lower layer) was washed (washed with saturated brine), dried, filtered, and concentrated by a rotary evaporator;

(3) The concentrate obtained in step (2) was subjected to silica gel column chromatography, and the volume ratio of dichloromethane:methanol=20:1 was used as the eluent to obtain 2,4,5-trisubstituted imidazole compound IV.

The reaction formula is:

in:

R ₁ is a monosubstituted aromatic ring, and the substituents can be halogen or hydrogen.

R ₂ is C1-C2 alkane.

R ₃ is hydrogen, C1-C2 alkanyl, monosubstituted aromatic ring (substituent can be halogen, alkoxy), benzyl (substituent can be alkoxy), heterocycle.

The 2,4,5-trisubstituted imidazole compound is any one of the following compounds:

5-Methyl-4-phenyl-1H-imidazole (Example 1)

5-Ethyl-4-phenyl- 1H -imidazole (Example 2)

4-(4-Chlorophenyl)-5-methyl-1 H -imidazole (Example 3)

4-(4-Chlorophenyl)-2,5-dimethyl-1 H -imidazole (Example 4)

4-(4-Bromophenyl)-5-methyl-1 H -imidazole (Example 5)

4-(4-Bromophenyl)-2,5-dimethyl-1 H -imidazole (Example 6)

5-Ethyl-2,4-diphenyl-1 H -imidazole (Example 7)

Preparation of 2-(4-methoxyphenyl)-5-methyl-4-phenyl-1H-imidazole (Example 8)

Preparation of 4-(4-fluorophenyl)-5-methyl-1H-imidazole (Example 9)

Preparation of 5-methyl-2,4-diphenyl-1H-imidazole (Example 10)

Preparation of 4-(4-chlorophenyl)-5-ethyl-1H-imidazole (Example 11)

Preparation of 5-ethyl-2,4-diphenyl-1H-imidazole 5-ethyl-2-(4-methoxyphenyl)-4-phenyl-1H-imidazole (Example 12)

Preparation of 2-(4-fluorophenyl)-5-methyl-4-phenyl-1H-imidazole (Example 13)

Preparation of 5-methyl-4-phenyl-2-(thiophen-2-yl)-1H-imidazole (Example 14)

The present invention provides a simple, rapid and diversified method for constructing 2,4,5-trisubstituted imidazole compounds, which involves reacting α-nitroepoxides with amidine compounds and bases at room temperature, The synthesis method of the present invention has no literature report. Compared with the existing synthetic methods of 2,4,5-trisubstituted imidazoles, this method has the following advantages: (1) The raw material α-nitroepoxide used in the reaction has a simple preparation method, and amidines and inorganic compounds used The bases are cheap and easy to obtain; (2) The reaction conditions are mild, without high temperature, high pressure and inert gas protection, and the reaction can be carried out only by stirring at room temperature; (3) The reaction does not require any expensive additives (such as various metal catalysts, etc.), just use The cheap and relatively common inorganic base sodium methoxide can provide the basic conditions required for the reaction; (4) The reaction is applicable to a wide range of functional groups such as aromatic rings, aliphatic chains, and heterocyclic rings; (5) The reaction is " "One-pot method", the steps are simple and easy to operate. The reaction raw materials in the method of the invention are cheap and easy to obtain, without any expensive additives (such as various metals), the target compound can be obtained by stirring at room temperature, and the yield is high.

Detailed ways

The present invention is described further in conjunction with embodiment.

Example 1: Preparation of 5-methyl-4-phenyl-1H-imidazole

1. Preparation of raw material 2-methyl-2-nitro-3-phenyloxirane

Add 2.1g (20mmol) of benzaldehyde and 9.0ml (100mmol) of nitroethane into a three-necked flask, and slowly add 0.3ml (2mmol) of Et ₃ N dropwise at room temperature. After the addition is complete, stir at room temperature under nitrogen protection for 18h . After the disappearance of raw materials detected by the TLC plate, the excess solvent was evaporated under reduced pressure, and the crude product α-nitroalcohol was directly dissolved in dichloromethane, and then 7.4 mL (42 mmol) of N,N-diisopropylethylamine and formaldehyde were added sequentially. Sulfonyl chloride 1.9 mL (24 mmol), after the addition, the reaction gradually returned to room temperature. After the TLC plate detected that the raw materials disappeared, the reaction system was extracted with dichloromethane, and the organic phase was washed twice with 10ml of 2M dilute hydrochloric acid and once with saturated brine, and combined The organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a yellow liquid crude product, which was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 15:1) to obtain a yellow solid (E)-1-phenyl-2-nitro Propylene, 85% yield.

Add 2.4 ml (42.8 mmol) of 50% hydrogen peroxide to 38 ml of anhydrous methanol and stir in an ice bath for 10 min, then add (E)-1-phenyl-2-nitropropene 2.0 g (12.1 mmol) and 2M NaOH solution 3.9 ml (6.1 mmol) was added sequentially under ice bath conditions, and then vigorously stirred for 10 min. After the disappearance of the raw material was detected by the TLC plate, 10 ml of ice water was added to the reaction system, and then extracted with ether (3 x 30 ml) and the organic phases were combined. The organic phase was washed once with 45 ml of saturated brine, and then dried over anhydrous sodium sulfate overnight. Filtration, evaporation of the solvent under reduced pressure gave a yellow oily liquid, the crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 15:1) to give a yellow oily liquid 2-methyl-2-nitro- 1.8 g of 3-phenyloxirane, yield 84%. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.41 (m, 3H), 7.30 (m, 2H), 4.56 (s, 1H), 1.78 (s, 3H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 131.0, 129.3, 128.7, 126.3, 88.8, 62.6, 12.2; IR (KBr) δ 3062, 3028, 2948, 1555, 1495, 1448, 1354, 1158, 1105, 982, ^899cm ₉ H ₉ NO ₃ (M) 179.0582, found 179.0587.

2. Preparation of 5-methyl-4-phenyl-1H-imidazole

Add 155mg (1.5mmol) of formamidine acetate and 162mg (3.0 mmol) of sodium methoxide to the reaction flask, then add 5ml of anhydrous methanol, stir at room temperature (25°C) for 1h, and then add 2-methyl-2-nitro -3-Phenyloxirane 180 mg (1 mmol), stirred at room temperature for 8 h. Thin-layer chromatography (TLC) detected the disappearance of raw materials, and evaporated the solvent under reduced pressure. The crude product was purified by column chromatography (eluent: dichloromethane/methanol = 20:1) to obtain 145 mg of a yellow solid with a yield of 92%. .

The structural formula of this 5-methyl-4-phenyl-1 H -imidazole is:

¹ H NMR (500 MHz, DMSO) δ 7.68-7.56 (m, 3H), 7.39 (dd, J = 10.7, 4.8 Hz, 2H), 7.25-7.19 (m, 1H), 2.37 (s, 3H). ¹³ C NMR (125 MHz, DMSO) δ 134.22, 128.85, 126.27, 126.04, 12.47. HRMS (ESI): m/z calcd for C ₁₀ H ₁₁ N ₂ [M+H] ⁺ :159.0917, found: 159.0915.

The following are control experiments under different conditions:

Comparative Example 1-1. Change the stirring reaction at 25°C overnight to 8h at 0°C, and the rest are the same as in Example 1. 49 mg of the product 5-methyl-4-phenyl-1 H -imidazole was obtained as a yellow solid, and the yield was 31%.

Comparative example 1-2, change the stirring reaction at 25°C overnight to 8h at 50°C, and the rest are the same as in Example 1. 145 mg of the product 5-methyl-4-phenyl-1 H -imidazole was obtained as a yellow solid, and the yield was 92%.

Comparative example 1-3, change sodium methylate from 3 equivalents to 1.5 equivalents, all the other are the same as embodiment 1. 82 mg of the product 5-methyl-4-phenyl-1 H -imidazole was obtained as a yellow solid, and the yield was 52%.

Comparative example 1-4, change sodium methylate into 4 equivalents by 3 equivalents, all the other are the same as embodiment 1. 145 mg of the product 5-methyl-4-phenyl-1 H -imidazole was obtained as a yellow solid, and the yield was 92%.

Comparative examples 1-5, using N,N-dimethylformamide instead of methanol, and the rest are the same as in Example 1. 131 mg of the product 5-methyl-4-phenyl-1 H -imidazole was obtained as a yellow solid, and the yield was 83%.

Comparative Examples 1-6, 1,4-dioxane was used instead of methanol, and the rest were the same as in Example 1. 8 mg of the product 5-methyl-4-phenyl-1 H -imidazole was obtained as a yellow solid, and the yield was 5%.

Comparative example 1-7, replace methyl alcohol with ethanol, all the other are the same as embodiment 1. 128 mg of the product 5-methyl-4-phenyl-1 H -imidazole was obtained as a yellow solid, and the yield was 81%.

Comparative example 1-8, replace methanol with acetonitrile, all the other are the same as embodiment 1. 55 mg of the product 5-methyl-4-phenyl-1 H -imidazole was obtained as a yellow solid, and the yield was 35%.

Comparative example 1-9, replace sodium methylate with sodium carbonate (3.0 mmol), all the other are the same as embodiment 1. 111 mg of 5-methyl-4-phenyl-1 H -imidazole was obtained with a yield of 70%.

Comparative example 1-10, replace sodium methylate with potassium carbonate (3.0 mmol), all the other are the same as embodiment 1. 134 mg of 5-methyl-4-phenyl-1 H -imidazole was obtained with a yield of 85%.

Comparative Example 1-11, cesium carbonate (3.0 mmol) was used instead of sodium methoxide, and the rest were the same as in Example 1. 120 mg of 5-methyl-4-phenyl-1 H -imidazole was obtained with a yield of 76%.

Comparative Example 1-12, sodium hydroxide (3.0 mmol) was used to replace sodium methoxide, and the rest were the same as in Example 1. 32 mg of 5-methyl-4-phenyl-1 H -imidazole was obtained with a yield of 20%.

Comparative Example 1-13, sodium hydride (3.0 mmol) was used instead of sodium methoxide, and the rest were the same as in Example 1. 137 mg of 5-methyl-4-phenyl-1 H -imidazole was obtained with a yield of 87%.

Comparative Example 1-14, the organic base Et ₃ N (3.0 mmol) was used instead of sodium methoxide, and the rest were the same as in Example 1. 96 mg of 5-methyl-4-phenyl-1 H -imidazole was obtained with a yield of 61%.

Comparative Example 1-15, the organic base DIEA (3.0 mmol) was used instead of sodium methoxide, and the rest were the same as in Example 1. 107 mg of 5-methyl-4-phenyl-1 H -imidazole was obtained with a yield of 68%.

Comparative example 1-16, reaction 2h instead of reaction 8h, the rest is the same as embodiment 1. 60 mg of 5-methyl-4-phenyl-1 H -imidazole was obtained with a yield of 38%.

Comparative example 1-17, reaction 6h instead of reaction 8h, the rest is the same as embodiment 1. 130 mg of 5-methyl-4-phenyl-1 H -imidazole was obtained with a yield of 82%.

The preparation of embodiment 2,5-ethyl-4-phenyl-1 H -imidazole

Replace 2-methyl-2-nitro-3-phenyloxirane with 2-ethyl-2-nitro-3-phenyloxirane, the molar weight remains the same, and the rest are the same as in Example 1. 163 mg of white solid 5-ethyl-4-phenyl-1 H -imidazole was obtained, with a yield of 95%. Its structural formula is:

¹ H NMR (500 MHz, DMSO) δ 7.61 (s, 1H), 7.58 (dd, J = 8.1, 1.0 Hz, 2H), 7.39 (dd, J = 10.7, 4.9 Hz, 2H), 7.25-7.19 (m , 1H), 2.76 (q, J = 7.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H). ¹³ C NMR (125 MHz, DMSO) δ 134.78, 134.52, 128.88, 126.60, 126.19, 19.49, 14.61. HRMS (ESI): m/z calcd for C ₁₁ H ₁₃ N ₂ [M+H] ⁺ :173.1073, found: 173.1073.

The preparation of embodiment 3,4-(4-chlorophenyl)-5-methyl- 1H -imidazole

Replace 2-methyl-2-nitro-3-phenyloxirane with 3-(4-chlorophenyl)-2-methyl-2-nitrooxirane, the molar weight remains unchanged, and the rest With embodiment 1. 171 mg of the product 4-(4-chlorophenyl)-5-methyl-1 H -imidazole was obtained as a yellow solid, with a yield of 89%. Its structural formula is:

¹ H NMR (500 MHz, DMSO) δ 12.11 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.60 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 2.38 ( s, 3H). ¹³ C NMR (125 MHz, DMSO) δ 134.40, 130.36, 128.80, 127.78, 12.21. HRMS (ESI): m/z calcd for C ₁₀ H ₁₀ ClN ₂ [M+H] ⁺ :193.0527, found: 193.0537.

The preparation of embodiment 4,4-(4-chlorophenyl)-2,5-dimethyl- 1H -imidazole

Replace 2-methyl-2-nitro-3-phenyloxirane with 3-(4-chlorophenyl)-2-methyl-2-nitrooxirane, and replace methyl acetate with acetamidine hydrochloride Amidine, the molar weight is constant, all the other are with embodiment 1. 185 mg of the product 4-(4-chlorophenyl)-2,5-dimethyl-1 H -imidazole was obtained as a yellow solid, with a yield of 90%. Its structural formula is:

¹ H NMR (500 MHz, DMSO) δ 11.74 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 2.32 (s, 3H), 2.25 ( s, 3H). ¹³ C NMR (125 MHz, DMSO) δ 131.65, 129.94, 128.74, 127.49, 14.17, 11.82. HRMS (ESI): m/z calcd for C ₁₁ H ₁₂ ClN ₂ [M+H] ⁺ : 207.0684, found: 207.0686.

The preparation of embodiment 5,4-(4-bromophenyl)-5-methyl- 1H -imidazole

Replace 2-methyl-2-nitro-3-phenyloxirane with 3-(4-bromophenyl)-2-methyl-2-nitrooxirane, the molar weight remains unchanged, and the rest With embodiment 1. 194 mg of white solid 4-(4-bromophenyl)-5-methyl-1 H -imidazole was obtained with a yield of 82%. Its structural formula is:

¹ H NMR (500 MHz, MeOD) δ 7.63 (s, 1H), 7.59-7.53 (m, 2H), 7.53-7.47 (m, 2H), 2.41 (s, 3H). ¹³ C NMR (125 MHz, MeOD ) δ 133.81, 132.92, 131.23, 128.08, 119.68, 10.27. HRMS (ESI): m/z calcd for C ₁₀ H ₁₀ BrN ₂ [M+H] ⁺ :237.0022 found: 237.0018.

Embodiment 6, the preparation of 4-(4-bromophenyl)-2,5-dimethyl-1 H -imidazole

Replace 2-methyl-2-nitro-3-phenyloxirane with 3-(4-bromophenyl)-2-methyl-2-nitrooxirane, and replace methyl acetate with acetamidine hydrochloride Amidine, the molar weight is constant, all the other are with embodiment 1. 215 mg of yellow solid 4-(4-bromophenyl)-2,5-dimethyl-1 H -imidazole was obtained with a yield of 86%. Its structural formula is:

¹ H NMR (500 MHz, MeOD) δ 7.54 (dd, J = 6.7, 1.8 Hz, 2H), 7.48-7.43 (m, 2H), 2.36 (s, 3H), 2.35 (s, 3H). HRMS (ESI ): m/z calcd for C ₁₁ H ₁₂ BrN ₂ [M+H] ⁺ :251.0178, found: 251.0172.

Embodiment 7, the preparation of 5-ethyl-2,4-diphenyl-1 H -imidazole

Replace 2-methyl-2-nitro-3-phenyloxirane with 2-ethyl-2-nitro-3-phenyloxirane, replace formamidine acetate with benzamidine hydrochloride, Molar weight is constant, and all the other are with embodiment 1. 74 mg of the product 5-ethyl-2,4-diphenyl-1 H -imidazole was obtained as a light yellow solid, with a yield of 30%. Its structural formula is:

¹ H NMR (500 MHz, DMSO) δ 12.34 (s, 1H), 7.99 (d, J = 5.4 Hz, 2H), 7.67 (s, 2H), 7.45 (dd, J = 16.7, 8.9 Hz, 4H), 7.33 (ddd, J = 44.7, 19.7, 18.6 Hz, 2H), 2.98-2.63 (m, 2H), 1.28 (t, J = 6.6 Hz, 3H). ¹³ C NMR (125 MHz, DMSO) δ 144.22, 136.13 , 131.12, 130.83, 129.12, 128.87, 128.29, 126.73, 126.30, 125.20, 18.90, 14.87. HRMS (ESI): m/z calcd for C ₁₀ H ₁₇ N ₂ [M+H] ⁺ :249.13246, found.

Example 8, Preparation of 2-(4-methoxyphenyl)-5-methyl-4-phenyl- 1H -imidazole

Replace formamidine acetate with p-methoxybenzamidine hydrochloride, the molar weight is constant, and all the other are the same as in Example 1. 108 mg of the yellow oily liquid product 2-(4-methoxyphenyl)-5-methyl-4-phenyl-1H-imidium was obtained with a yield of 41%.

Its structural formula is:

¹ H NMR (500 MHz, CDCl ₃ ) δ 10.39 (s, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.6 Hz , 2H), 7.23 (t, J = 7.3 Hz, 1H), 6.82 (d, J = 8.6 Hz, 2H), 3.77 (s, 3H), 2.34 (s, 3H). ¹³ C NMR (125 MHz, CDCl ₃ ) δ 159.71, 145.61, 133.33, 132.97, 128.45, 126.94, 126.38, 123.18, 114.12, 55.27, 12.09. HRMS (ESI): m/z calcd for C ₁₇ H ₁₅₇ N ₂ O: [M+H] ⁺ 1 , found: 265.1335.

Example 9, Preparation of 4-(4-fluorophenyl)-5-methyl- 1H -imidazole

Replace 2-methyl-2-nitro-3-phenyloxirane with 3-(4-fluorophenyl)-2-methyl-2-nitrooxirane, the molar weight remains unchanged, and the rest With embodiment 1. 120 mg of the product 4-(4-fluorophenyl)-5-methyl- 1H -imidazole was obtained as a yellow solid, with a yield of 68%. Its structural formula is:

¹ H NMR (500 MHz, DMSO) δ 12.05 (s, 1H), 7.67-7.60 (m, 2H), 7.58 (s, 1H), 7.24 -7.19 (m, 2H), 2.36 (s, 3H).HRMS (ESI): m/z calcd for C ₁₀ H ₁₀ FN ₂ [M+H] ⁺ :177.0823, found: 177.0822.

Example 10, Preparation of 5-methyl-2,4-diphenyl- 1H -imidazole

Substitute formamidine acetate with benzamidine hydrochloride, the molar weight is constant, and all the other are the same as in Example 1. 77 mg of the product 5-methyl-2,4-diphenyl- 1H -imidazole was obtained as a white solid, with a yield of 33%. Its structural formula is:

¹ H NMR (500 MHz, DMSO) δ 12.42 (s, 1H), 8.00 (d, J = 7.5 Hz, 2H), 7.71 (d, J = 7.1 Hz, 2H), 7.51-7.39 (m, 4H), 7.38-7.30 (m, 1H), 7.25 (t, J = 7.3 Hz, 1H), 2.46 (s, 3H). ¹³ C NMR (125 MHz, DMSO) δ 144.16, 131.09, 129.16, 128.87, 128.26, 126.40, 126.55, 126.25, 125.11, 12.12. HRMS (ESI): m/z calcd for C ₁₆ H ₁₅ N ₂ [M+H] ⁺ :235.1235, found: 235.1233.

Example 11, Preparation of 4-(4-chlorophenyl)-5-ethyl- 1H -imidazole

Replace 2-methyl-2-nitro-3-phenyloxirane with 3-(4-chlorophenyl)-2-ethyl-2-nitrooxirane, the molar weight remains unchanged, and the rest With embodiment 1. 171 mg of the product 4-(4-chlorophenyl)-5-ethyl- 1H -imidazole was obtained as a yellow solid, with a yield of 83%. Its structural formula is:

¹ H NMR (500 MHz, DMSO) δ 7.64 (s, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.49-7.36 (m, 3H), 2.76 (q, J = 7.5 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H). ¹³ C NMR (125 MHz, DMSO) δ 160.91, 134.70, 130.59, 128.87, 128.62, 128.12, 14.43. HRMS (ESI): m/z calcd for C ₁₁ H ₁₂ ClN ₂ [M+H] ⁺ :207.0684, found: 207.0690.

Example 12, Preparation of 5-ethyl-2,4-diphenyl- 1H -imidazole 5-ethyl-2-(4-methoxyphenyl)-4-phenyl- 1H -imidazole

Replace 2-methyl-2-nitro-3-phenyloxirane with 2-ethyl-2-nitro-3-phenyloxirane, p-methoxyphenacetamidine hydrochloride instead Formamidine acetate, molar weight is constant, all the other are with embodiment 1. Obtain 190 mg of yellow solid product 5-ethyl-2,4-diphenyl-1 H -imidazole 5-ethyl-2-(4-methoxyphenyl)-4-phenyl- 1H -imidazole. The rate is 65%. Its structural formula is:

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.78 (s, 1H), 7.48 – 7.45 (m, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.24 (dd, J = 12.8, 5.5 Hz, 1H), 7.15 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 4.01 (s, 2H), 3.69 (s, 3H), 2.70 (q, J = 7.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H). ¹³ C NMR (500 MHz, CDCl ₃ )δ 158.55, 146.08, 129.96, 129.49, 128.63, 128.44, 127.88, 127.08, 55.17, 124.60, 5. HRMS (ESI): m/z calcd for C ₁₉ H ₂₁ N ₂ O [M+H] ⁺ : 293.1654, found: 293.1644.

Example 13, Preparation of 2-(4-fluorophenyl)-5-methyl-4-phenyl- 1H -imidazole

Substitute formamidine acetate with p-fluorobenzamidine hydrochloride, the molar weight remains unchanged, and the rest are the same as in Example 1. 63 mg of the product 2-(4-fluorophenyl)-5-methyl-4-phenyl- 1H -imidazole was obtained as a light yellow solid, with a yield of 25%.

Its structural formula is:

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.77 (dd, J = 8.6, 5.3 Hz, 2H), 7.56 (d, J = 7.8 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.28 (d, J = 8.2 Hz, 1H), 6.98 (t, J = 8.4 Hz, 2H), 2.38 (s, 3H). ¹³ C NMR (126 MHz, CDCl ₃ ) δ 163.78, 161.81, 144.45, 132.93, 128.57 , 127.19, 126.92, 126.71, 126.41, 115.83, 115.66, 12.17. HRMS (ESI): m/z calcd for C ₁₆ H ₁₄ FN ₂ [M+H] ⁺ :253.1141, found: 253.1140.

Example 14, Preparation of 5-methyl-4-phenyl-2-(thiophen-2- yl )-1H-imidazole

Thiophene-2-formamidine hydrochloride was used instead of formamidine acetate, and the molar weight remained the same, and the rest were the same as in Example 1. 108 mg of the product 5-methyl-4-phenyl-2-(thiophen-2- yl )-1H-imidazole was obtained as a light yellow solid, and the yield was 45%.

Its structural formula is:

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.56 (d, J = 7.4 Hz, 2H), 7.44 (d, J = 3.1 Hz, 1H), 7.37 (t, J = 7.7 Hz, 2H), 7.28-7.20 (m, 2H), 6.99 (dd, J = 4.7, 3.9 Hz, 1H), 2.41 (s, 3H). ¹³ C NMR (125 MHz, CDCl ₃ ) δ 140.85, 133.49, 132.71, 128.55, 127.70, 126.88, 126.64, 125.54, 124.02, 12.35. HRMS (ESI): m/z calcd for C ₁₆ H ₁₃ N ₂ S [M+H] ⁺ :241.0799, found: 241.0799.

Claims (6)

1. one kind 2,4, the preparation method of 5-tri-substituted imidazoles, is characterized in that, amidine compound II and alkali III is stirred 1 hour in corresponding solvent, then add α-nitro epoxide I and carry out ring-closure reaction 3-12 hour in 25 DEG C, thus obtain 2,4,5-tri-substituted imidazoles IV, gained target product is by the method purifying of silica gel chromatography column chromatography, and methylene chloride/methanol is eluent; Reaction formula:

Wherein:

R ₁for mono-substituted aromatic ring, substituting group can be halogen, hydrogen,

R ₂for C1-C2 paraffinic hydrocarbons,

R ₃for hydrogen, C1-C2 alkyl group, monosubstituted aromatic ring, benzyl, heterocycle, wherein the substituting group of monosubstituted aromatic ring selects halogen, alkoxyl group, and benzyl selects substituting group to be alkoxyl group.

2. the preparation method of a kind of 2,4,5-tri-substituted imidazoles according to claim 1, be is characterized in that, realized by following steps:

(1) just amidine compound II and alkali III stir 1 hour in a solvent, then α-nitro epoxide I is added, carry out ring-closure reaction in 25 DEG C, the reaction times is 3-12 hour, and the mol ratio of wherein α-nitro epoxide, amidine compound, alkali is 1:1.5:3;

(2), after the reaction solution chloroform extraction of step (1) gained, the organic layer of gained is through with dry after saturated common salt water washing, and filter, Rotary Evaporators concentrates;

(3) step (2) gained enriched material is carried out silica gel column chromatography separation, methylene chloride/methanol is eluent, obtains 2,4,5-tri-substituted imidazoles IV; Reaction formula:

Wherein:

R ₁for mono-substituted aromatic ring, substituting group can be halogen, hydrogen,

R ₂for C1-C2 paraffinic hydrocarbons,

R ₃for hydrogen, C1-C2 alkyl group, monosubstituted aromatic ring, benzyl, heterocycle, wherein the substituting group of monosubstituted aromatic ring selects halogen, alkoxyl group, and benzyl selects substituting group to be alkoxyl group.

3. according to claim 1 and 2 a kind of 2,4, the preparation method of 5-tri-substituted imidazoles, it is characterized in that, step (1) described solvent is polar solvent or non-polar solvent, and described polar solvent selects methyl alcohol, ethanol, n-propyl alcohol, propyl carbinol, Virahol, the trimethyl carbinol, isopropylcarbinol, Pentyl alcohol, ethylene glycol or acetonitrile; Non-polar solvent selects ether or tetracol phenixin.

4. the preparation method of a kind of 2,4,5-tri-substituted imidazoles according to claim 1 and 2, is characterized in that: the silica gel column chromatography of described step (3) is: using methylene dichloride: the volume ratio of methyl alcohol=20:1 is as elutriant.

5. the preparation method of a kind of 2,4,5-tri-substituted imidazoles according to claim 1 and 2, is characterized in that: methyl alcohol selected by step (1) described solvent.

6. the preparation method of a kind of 2,4,5-tri-substituted imidazoles according to claim 1 and 2, is characterized in that: the described solvent alkali II of step (1) selects sodium methylate.