19/02/2022, 17:59 CN104844518 一种2,4,5‑三取代的咪唑类化合物的制备方法

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1. CN104844518 - 一种2,4,5‑三取代的咪唑类化合物的
制备方法
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​[ZH]
​Preparation method of 2,4,5-trisubstituted imidazole compound

         ​Technical field

         ​The invention belongs to the synthesis method of compounds, and mainly relates to a preparation method of 2, 4, 5-
trisubstituted imidazole compounds
         ​BACKGROUND OF THE INVENTION
         ​Imidazole is used as a five-membered aromatic heterocyclic compound, and has wide application in the fields of medicines,
pesticides, materials, fine chemical industry and the like.. The polysubstituted imidazole, especially the 2,4,5-trisubstituted imidazole
compound, is a very important imidazole compound as an excellent synthetic building block, which plays a crucial role in the
synthesis of numerous anti-tumor, anti-bacterial, anti-fungal, anti-virus and anti-inflammatory drugs.
         ​Since the 2,4,5-trisubstituted imidazole compound has very important application value, the synthesis method is always a hot
spot in the synthesis field, and the new method in recent years is not exhaustive
         ​(1) a microwave-assisted multi-substituted imidazole synthesis method (Scott) E Wolfrenberg et al. William Kleh Leister, Org.. Lett.
2004, 6, 1453-1456).
        
         ​Formula 1, Scott (Scott) E Wolkenberg microwave-assisted 2, 4, 5-trisubstituted imidazole synthesis method
         ​According to the method, 1,2-diketone and aldehyde and ammonium acetate which are difficult to prepare are used as raw
materials, microwave-assisted method is adopted for synthesis under high-temperature conditions, and the method is not suitable for
large-scale mass production
         ​The method comprises the following steps: (2) taking alpha-hydroxyketone, benzyl alcohol and ammonium acetate as raw
materials by Arislan, Mirjari, and the like, carrying out microwave reaction in the ionic liquid, and finally obtaining a series of 2,4,5-
trisubstituted imidazole compounds (Arsalan, Mirjarjari, and Nvicon HEM Lett. (2014) 12: 177-183).
        
         ​The method comprises the following steps of: 2, Arislan, Mirjari,2,4, 5-trisubstituted imidazole synthesis method
         ​The reaction also needs a microwave-assisted reaction under a high-temperature condition, and the conditions are relatively
harsh
         ​The preparation method comprises the following steps: (3) taking alpha-nitroolefins and amidine compounds, such as
Shubhhanjan, Mitra and the like as raw materials, taking nano In2O3 as a reaction catalyst, and synthesizing a 2,4,5-trisubstituted
imidazole compound under a heating condition (Shubhanjan Mitra, Adinath, Majee, Adinath, Majee, Alankangda, Haja). Tetrahedron
Lett. 2013, 54, 4982-4985).
        
         ​Formula 3, Shubhanjan, Mitra -2, 4,5-trisubstituted imidazole synthesis method
         ​According to the method, expensive nano In2O3 is used as a catalyst, and the reaction needs higher temperature to take place.
         ​Although the synthetic report of the 2,4,5-trisubstituted imidazole compound is more reported, the known synthesis method still
exists that the raw materials are not easy to obtain, the catalyst with large toxicity is used, the product yield is low, and the
preparation method of the novel 2,4,5-trisubstituted imidazole compound has the advantages that the novel 2,4,5-trisubstituted
imidazole compound is developed
         ​SUMMARY OF THE INVENTION
         ​The technical problem to be solved by the invention is to provide a preparation method of a 2,4,5-trisubstituted imidazole
compound. The preparation method comprises the following steps: reacting an alpha-nitrogenous epoxide with an amidine compound
and an alkali under the room temperature condition, namely reacting an easily-chemically synthesized 2,3-disubstituted-2-
nitrogenous ethylene oxide compound and an amidine compound at room temperature
        
         ​Structural general formula of 2, 4, 5-trisubstituted imidazole compound
         ​The preparation method of the 2,4,5-trisubstituted imidazole compound provided by the invention comprises the following steps:
stirring the amidine compound II and the base III in a corresponding solvent for 1 hour, then adding alpha-nitrogenous epoxide I, and
carrying out cyclization reaction for 3-12 (preferably 8H) to obtain the 2,4,5-trisubstituted imidazole compound IV. The alkali used is
sodium methoxide. The reaction temperature is 25 DEG C at room temperature. The solvent used is a polar solvent or a nonpolar
solvent, and the polar solvent is selected from methanol, ethanol, n-propanol, n-butanol, isopropanol, tert-butanol, isobutanol, n-
amyl alcohol, ethylene glycol or acetonitrile; and the non-polar solvent is selected from diethyl ether or carbon tetrachloride. In
general, methanol ​The obtained target product is purified by means of silica gel chromatography column chromatography
(dichloromethane/methanol as eluent).
         ​The preparation method comprises the following specific steps:

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19/02/2022, 17:59 CN104844518 一种2,4,5‑三取代的咪唑类化合物的制备方法
         ​(1) carrying out a cyclization reaction on alpha-nitrogenous epoxide I, an amidine compound II and an alkali II (for example,
sodium methoxide) at 25 DEG C, wherein the reaction time is 3-12 hours, wherein the molar ratio of the alpha-nitro epoxide to the
amidine compound to the base is 1: 1.5: 3;
         ​(2) after the reaction liquid obtained in the step (1) is extracted with chloroform, the obtained organic layer (located at the lower
layer) is washed (washed with saturated brine), then dried, filtered, and the rotary evaporator is concentrated;
         ​(3) carrying out silica gel column chromatography separation on the concentrate obtained in the step (2), and taking
dichloromethane: methanol = 20: 1 in a volume ratio as eluent to obtain the 2,4,5-trisubstituted imidazole compound IV
         ​The reaction formula is as follows:
        
         ​The method comprises the following steps:
         ​R1 is a mono-substituted aromatic ring, and the substituent can be halogen and hydrogen
         ​R2 is C1-C2 paraffins
         ​R 3 is hydrogen, C1-C2 chain alkyl, mono-substituted aromatic ring (the substituent can be halogen, alkoxy), benzyl (substituent
can be alkoxy), and heterocycle
         ​The 2,4,5-trisubstituted imidazole compound is any one of the following compounds:
        5 ​-methyl -4-phenyl -1 H-imidazole (example 1)
        5 ​-ethyl -4-phenyl -1 H-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)
        2 ​Preparation of (4-methoxyphenyl)-5-methyl-4-phenyl -1 H-imidazole (example 8)
        4 ​Preparation of (4-fluorophenyl)-5-methyl -1 H-imidazole (example 9)
        5 ​Preparation of methyl -2,4-diphenyl -1 H-imidazole (example 10)
        4 ​Preparation of (4-chlorophenyl)-5-ethyl -1 H-imidazole (example 11)
        5 ​Preparation of ethyl -2,4-diphenyl -1 H-imidazole 5-ethyl-2-(4-methoxyphenyl)-4-phenyl -1 H-imidazole (example 12)
        2 ​Preparation of (4-fluorophenyl)-5-methyl-4-phenyl -1 H-imidazole (example 13)
        5 ​Preparation of methyl-4-phenyl-2-(thiophen-2-yl) -1 H-imidazole (example 14)
         ​The invention provides a simple, rapid and diversified method for constructing the 2,4,5-trisubstituted imidazole compound. The
synthesis method of the invention is not reported in the literature.. Compared with the synthesis method of the existing 2,4,5-
trisubstituted imidazole compound, the method has the following advantages: (1) the preparation method of the raw material alpha-
nitrogenous epoxide used in the reaction is simple, the amidine compound and the inorganic base are cheap and easy to obtain; (2)
the reaction condition is mild, high-temperature and high-pressure and inert gas protection are not needed, and the reaction can be
carried out only by stirring at room temperature; and (3) the reaction does not need any expensive additive (such as various metal
catalysts and the like) ​The method has the advantages that only the use price is low, and the basic conditions required for the reaction
are provided for the common inorganic base sodium methoxide; (4) the reaction application range is wide, and the method is suitable
for various functional groups such as aromatic rings, fatty chains and heterocyclic rings; and (5) the reaction is "one-pot method", and
the steps are simple and easy to operate.. According to the method, the reaction raw materials are cheap and easy to obtain, any
expensive additive (such as various metals) is not needed, the target compound can be obtained through stirring at room
temperature, and the yield is high.
         ​DETAILED DESCRIPTION OF THE EMBODIMENTS
         ​DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION
         ​Preparation of 5-methyl-4-phenyl -1 H-imidazole
        1、 ​Preparation of raw material 2-methyl-2-nitro-3-phenyl ethylene oxide
         ​The preparation method comprises the following steps: adding 2.1 g (20 mmol) of benzaldehyde and 9.0 mL (100 mmol) of
nitrobenzene into a three-necked bottle, slowly dropwise adding 0.3 mL (2 mmol) of Et3 N in a room temperature condition, carrying
out nitrogen protection at the room temperature, stirring at room temperature for 18h, and stirring at room temperature for 18h; after
the TLC plate detects that the raw material disappears, evaporating the excess solvent under reduced pressure, and then sequentially
adding N, N-diisopropylethylamine 7.4 mL (42 mmol) and methylsulfonyl chloride 1 9 ​ML (24 mmol), the reaction is gradually restored to
room temperature after feeding, the reaction system is extracted with dichloromethane, the organic phase is washed twice with 10 ml
of 2M dilute hydrochloric acid, the saturated salt water is washed once, the organic phase is combined, and anhydrous sodium sulfate
is dried. The solvent is evaporated under reduced pressure to obtain a yellow liquid crude product which is purified by column
chromatography (eluent: petroleum ether/ethyl acetate = 15: 1) to obtain yellow solid (E)-1-phenyl-2-nitropropylene, and the yield is
85%
         ​50% of hydrogen peroxide 2.4 mL (42.8 mmol) is added into 38 mL of anhydrous methanol in an ice bath for stirring for 10 min,
then (E)-1-phenyl-2-nitropropylene 2.0 g (12.1 mmol) and 2 M of African solution (3.9 mL (6.1 mmol)) are sequentially added, then
vigorous stirring is conducted for 10 min, the to-be-monitored TLC plate detects that the raw materials disappear, ice water is added to
the reaction system for 10 mL, and then extracted with diethyl ether (30 mL) and combined with an organic phase. The organic phase
is washed once with 45 mL of saturated brine, and dried overnight with anhydrous sodium sulfate ​filtering, and removing the solvent
under reduced pressure to obtain a yellow oily liquid, wherein the crude product is purified by column chromatography (eluent:
petroleum ether/ethyl acetate = 15: 1) to obtain the yellow oily liquid 2-methyl-2-nitro-3-phenyl ethylene oxide 1.8 g, and the yield is
84%. 1 H NMR delta 7.41 (m, 3), 7.30 (m, 2H), 4.56 (s, 1H), 1 78 ​13 C NMR delta 131.0, 129.3, 128.7, 126.3, 88.8, 62.6, 12.2; IR delta
3062,3028,2948, 1555,1495,1448, 1354,1158,1105, 982, 899 cm -1 ​; HRMS (EI) calcd for C 9 H9 NO. 3 (M) 179.0582, Found 179.0587.
        2、 ​Preparation of 5-methyl-4-phenyl -1 H-imidazole
         ​The preparation method comprises the following steps: adding 155 mg (1.5 mmol) of formamidine acetate and 162 mg (3.0 mmol)
of sodium methoxide into a reaction bottle, adding 5 mL of anhydrous methanol, stirring at normal temperature (25 DEG C) for 1h, then
adding 180 mg (1 mmol) of 2-methyl-2-nitro-3-phenyl ethylene oxide, stirring at room temperature for 8 h, detecting the
disappearance of the raw material, removing the solvent under reduced pressure, and carrying out column chromatography
purification on the crude product (eluent): dichloromethane/methanol = 20: 1) to obtain the yellow solid 145 mg, and the yield is 92%.
         ​Structural formula of 5-methyl-4-phenyl -1 H-imidazole is as follows:
        
         1 ​H NMR delta 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, 3). 13 C NMR delta 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. 
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19/02/2022, 17:59 CN104844518 一种2,4,5‑三取代的咪唑类化合物的制备方法
         ​Control experiments with different conditions are as follows:
         ​The preparation method comprises the following steps: carrying out stirring reaction at 25 DEG C overnight at a temperature of 0
DEG C for 8 hours, and obtaining the yellow solid product 5-methyl-4-phenyl -1 H-imidazole 49 mg and the yield of 31%.
         ​The preparation method comprises the following steps: carrying out stirring reaction at 25 DEG C overnight, and stirring at 50 DEG
C for reaction for 8 h; and the rest of the same embodiment 1 can obtain the yellow solid product 5-methyl-4-phenyl -1 H-imidazole 145
mg, and the yield is 92%.
         ​The ratio is 1-3, the sodium methoxide is changed to 1.5 equivalents from 3 equivalents, and the rest is the same as that in
Example 1 to obtain the yellow solid product 5-methyl-4-phenyl -1 H-imidazole 82 mg, and the yield is 52%.
         ​The ratio is 1-4, the sodium methoxide is changed to 4 equivalents from 3 equivalents, and the rest is the same as that in Example
1 to obtain the yellow solid product 5-methyl-4-phenyl -1 H-imidazole 145 mg, and the yield is 92%.
         ​The preparation method comprises the following steps: replacing methanol with N, N-dimethylformamide to obtain yellow solid
product 5-methyl-4-phenyl -1 H-imidazole 131 mg, and yield 83%.
         ​The preparation method comprises the following steps: replacing methanol with 1,4-dioxane with 1,4-dioxane to obtain the yellow
solid product 5-methyl-4-phenyl -1 H-imidazole 8 mg and the yield of 5%.
         ​The ratio is 1-7, methanol is replaced by ethanol, and the rest is the same as that in Example 1 to obtain the yellow solid product
5-methyl-4-phenyl -1 H-imidazole 128 mg, and the yield is 81%.
         ​Comparative Example 1-8: replacing methanol with acetonitrile, and the rest is the same as that of Example 1 to obtain the yellow
solid product 5-methyl-4-phenyl -1 H-imidazole 55 mg, and the yield is 35%.
         ​The ratio is 1-9, sodium carbonate (3.0 mmol) is used for replacing sodium methoxide, and the rest of the same is the same as
that in Example 1 to obtain 5-methyl-4-phenyl -1 H-imidazole 111 mg, and the yield is 70%.
         ​The ratio is 1-10, potassium carbonate (3.0 mmol) is used to replace sodium methoxide, and the rest of the same is the same as
that in Example 1 to obtain 5-methyl-4-phenyl -1 H-imidazole 134 mg, and the yield is 85%.
         ​Comparative Example 1-11: replacing sodium methoxide with cesium carbonate (3.0 mmol), and the balance being 5-methyl-4-
phenyl -1 H-imidazole 120 mg, yield 76%.
         ​For the comparative examples 1-12, sodium hydroxide (3.0 mmol) is used to replace sodium methoxide, and the rest of the same
is the same as that in Example 1 to obtain the 5-methyl-4-phenyl -1 H-imidazole 32 mg, and the yield is 20%.
         ​Comparative Example 1-13: Sodium hydride (3.0 mmol) was used to replace sodium methoxide, and the rest of the same Example
1 gave 5-methyl-4-phenyl -1 H-imidazole 137 mg, yield 87%.
         ​Comparative Example 1-14: replacing sodium methoxide with an organic base Et3 N (3.0 mmol), and the balance being 5-methyl-
4-phenyl -1 H-imidazole 96 mg, and the yield is 61%.
         ​Comparative Example 1-15: replacing sodium methoxide with organic alkali DIEA (3.0 mmol), and the rest of the same in Example 1
gave 5-methyl-4-phenyl -1 H-imidazole 107 mg, and the yield is 68%.
         ​For the comparative examples 1-16, the reaction is carried out for 2h instead of the reaction for 8 h, and the rest of the same
Example 1 results in 60 mg of 5-methyl-4-phenyl -1 H-imidazole and 38% of yield.
         ​For the comparative examples 1-17, the reaction is carried out for 6 hours to replace the reaction for 8 h, and the rest of the same
embodiment 1 results in 5-methyl-4-phenyl -1 H-imidazole 130 mg, and the yield is 82%.
         ​Preparation of 5-ethyl-4-phenyl -1 H-imidazole
         ​2-ethyl-2-nitro-3-phenyl ethylene oxide is used instead of 2-methyl-2-nitro-3-phenyl ethylene oxide, the molar amount is not
changed, and the rest is the same as embodiment 1 to obtain the white solid 5-ethyl-4-phenyl -1 H-imidazole 163 mg and the yield is
95%. The structural formula is as follows:
        
         1 ​H NMR delta 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, 3 H). 13 C NMR delta 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.
         ​Preparation of 4-(4-chlorophenyl)-5-methyl -1 H-imidazole
         ​The preparation method comprises the following steps: replacing 2-methyl-2-nitro-3-phenyl ethylene oxide with 3-(4-
chlorophenyl)-2-methyl-2-nitrooxirane,
oxir wherein the molar amount is not changed, and the rest is the same as that in Embodiment 1 to
obtain the 4-(4-chlorophenyl)-5-methyl -1 H-imidazole 171 mg of the yellow solid product, and the yield is 89%. The structural formula
is as follows:
        
         1 ​H NMR delta 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, 3). 13 C NMR delta 134.40, 130.36,
128.80, 127.78, 12.21. ​HRMS (ESI): m/z calcd for C 10H 10 [M + H] +: 193.0527, Found: 193.0537.
         ​Preparation of 4-(4-chlorophenyl) -2,5-dimethyl -1 H-imidazole
         ​The preparation method comprises the following steps: replacing 2-methyl-2-nitro-3-phenyl ethylene oxide with 3-(4-
chlorophenyl)-2-methyl-2-nitroethylene oxide, replacing formamidine hydrochloride with acetamidine hydrochloride, wherein the
molar amount is not changed, and the rest of the same is the same as that in Embodiment 1 to obtain the yellow solid product 4-(4-
chlorophenyl) -2,5-dimethyl -1 H-imidazole 185 mg, and the yield is 90%.. The structural formula is as follows:
        
         1 ​H NMR delta 11.74 (s, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 2.32 (s, 3), 2.25 (s, 3). 13 C NMR delta 131.65, 129.94, 128.74,
127.49, 14 17, ​11.82. HRMS [M + H] +: 207.0684, Found: 207.0686.
         ​Preparation of 4-(4-bromophenyl)-5-methyl -1 H-imidazole
         ​The preparation method comprises the following steps: replacing 2-methyl-2-nitro-3-phenyl ethylene oxide with 3-(4-
bromophenyl)-2-methyl-2-nitrooxirane,
oxir wherein the molar amount is not changed, and the rest of the same is the same as
embodiment 1 to obtain the white solid 4-(4-bromophenyl)-5-methyl -1 H-imidazole 194 mg and the yield 82%. The structural formula
is as follows:
        
         1 ​H NMR delta 7.63 (s, 1H), 7.59-7.53 (m, 2H), 7.53-7.47 (m, 2H), 2.41 (s, 3). 13 C NMR delta 133.81, 132.92, 131.23, 128.08, 119.68, 10.27. ​
HRMS (ESI): m/z calcd for C 10 H 10 R 2 [M + H] +: 237.22 found: 237.18.
         ​Preparation of 4-(4-bromophenyl) -2,5-dimethyl -1 H-imidazole
         ​The preparation method comprises the following steps: replacing 2-methyl-2-nitro-3-phenyl ethylene oxide with 3-(4-
bromophenyl)-2-methyl-2-nitroethylene oxide, replacing formamidine hydrochloride with acetamidine hydrochloride, wherein the
molar amount is not changed, and the rest of the same is the same as embodiment 1 to obtain the yellow solid 4-(4-bromophenyl)
-2,5-dimethyl -1 H-imidazole 215 mg and the yield of 86%. The structural formula is as follows:
         
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19/02/2022, 17:59 CN104844518 一种2,4,5‑三取代的咪唑类化合物的制备方法
         1 ​H NMR delta 7.54 (dd, J = 6.7, 1.8 Hz, 2H), 7.48-7.43 (m, 2H), 2.36 (S,3H), 2.35 (s, 3). ​HRMS (ESI): m/z calcd for C 11 H 12 R 2 [M + H] +:
251.0178, found: 251.0172.
         ​Preparation of 5-ethyl -2,4-diphenyl -1 H-imidazole
         ​2-ethyl-2-nitro-3-phenyl ethylene oxide is used for replacing 2-methyl-2-nitro-3-phenyl ethylene oxide and benzamidine
hydrochloride to replace formamidine acetate, the molar amount is not changed, and the rest of the same is the light yellow solid
product 5-ethyl -2,4-diphenyl -1 H-imidazole 74 mg, and the yield is 30%.. The structural formula is as follows:
        
         1 ​H NMR delta 12.34 (s, 1H), 7.99 (d, J = 5.4 Hz, 2H), 7.67 (d, J = 5.4 Hz, 2H), 7.67 (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 delta 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 10H 17 N 2 [M + H] +: 249.1386, found: 249.1380.
         ​Preparation of 2-(4-methoxyphenyl)-5-methyl-4-phenyl -1 H-imidazole
         ​The method comprises the following steps: replacing formamidine acetate with p-methoxyphenylformamidine hydrochloride,
wherein the molar amount is not changed, and the rest of the same is the same as that in Embodiment 1 to obtain the 2-(4-
methoxyphenyl)-5-methyl-4-phenyl -1 H-imidazole 108 mg and the yield of 41%.
         ​The structural formula thereof is as follows:
        
         1 ​H NMR delta 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, 3). 13 C NMR delta 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 H17 N 2 O [M + H] +: 265.1335, found: 265.1335.
         ​Preparation of 4-(4-fluorophenyl)-5-methyl -1 H-imidazole
         ​The preparation method comprises the following steps: replacing 2-methyl-2-nitro-3-phenyl ethylene oxide with 3-(4-
fluorophenyl)-2-methyl-2-nitrooxirane,
oxir wherein the molar amount is not changed, and the rest is the same as that in Embodiment 1 to
obtain the yellow solid product 4-(4-fluorophenyl)-5-methyl -1 H-imidazole 120 mg, and the yield is 68%.. The structural formula is as
follows:
        
         1 ​H NMR Delta 12.05 (S, 1H), 7.67-7.60 (m, 2H), 7.58 (s, 1H), 7.24-7.19 (m, 2H), 2.36 (s, 3). HRMS (ESI): m/z calcd for C 10 H10 FN 2 [M + H]
+: 177 0823, ​Found: 177.0822.
         ​Preparation of 5-methyl -2,4-diphenyl -1 H-imidazole
         ​Formamidine hydrochloride is used for replacing formamidine acetate, the molar amount is not changed, and the rest is the
same as embodiment 1 to obtain the white solid product 5-methyl -2,4-diphenyl -1 H-imidazole 77 mg and the yield is 33%. The
structural formula is as follows:
        
         1 ​H NMR delta 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 (1 H),
2.46 (s, 3). 13 C NMR delta 144.16, 131.09, 129.16, 128.87, 128.26, 126.40, 126.55, 126.25, 125.11, 12.12. ​HRMS (ESI): m/z Calc for C 16 H 15 N 2
[M + H] +: 235.1235, Found: 235.1233.
         ​Preparation of 4-(4-chlorophenyl)-5-ethyl -1 H-imidazole
         ​The preparation method comprises the following steps: replacing 2-methyl-2-nitro-3-phenyl ethylene oxide with 3-(4-
chlorophenyl)-2-ethyl-2-nitrooxirane,
oxir wherein the molar amount is not changed, and the rest is the same as that in Embodiment 1 to
obtain the 4-(4-chlorophenyl)-5-ethyl -1 H-imidazole 171 mg of the yellow solid product, and the yield is 83%. The structural formula is
as follows:
        
         1 ​H NMR delta 7.64 (s, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.49-7.36 (m, 3), 2.76 (q, J = 7.5 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H). 13 ​C NMR delta
160.91, 134.70, 130.59, 128.87, 128.62, 128.12, 14.43. HRMS (ESI): m/z calcd for C 11 H12 [M + H] +: 207.0684, Found: 207.0690.
         ​Preparation of 5-ethyl -2,4-diphenyl -1 H-imidazole 5-ethyl-2-(4-methoxyphenyl)-4-phenyl -1 H-imidazole
         ​The preparation method comprises the following steps: replacing 2-methyl-2-nitro-3-phenyl ethylene oxide with 2-ethyl-2-nitro-
3-phenyl ethylene oxide, replacing formamidine acetate with methoxyphenylacetamidine hydrochloride, wherein the molar amount is
not changed, and the rest is the same as embodiment 1 to obtain the yellow solid product 5-ethyl -2,4-diphenyl -1 H-imidazole 5-ethyl-
2-(4-methoxyphenyl)-4-phenyl -1 H-imidazole 190 mg and the yield of 65%. The structural formula is as follows:
        
         1 ​H NMR Delta 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 (d, J = 7.5 Hz, 2H), 2.70 (q, J = 7.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H). 13 ​C NMR delta 158.55, 146.08, 129.96, 129.49, 128.63,
128.44, 127.88, 127.08, 55.17, 32.63, 18.93, 14.05. ​HRMS (ESI): m/z calcd for C 19 H 21 N 2 O [M + H] +: 293.1654, found: 293.1644.
         ​Preparation of 2-(4-fluorophenyl)-5-methyl-4-phenyl -1 H-imidazole
         ​The p-fluorobenzamidine hydrochloride is used for replacing formamidine acetate, the molar amount is not changed, and the rest
of the same is the light yellow solid product 2-(4-fluorophenyl)-5-methyl-4-phenyl -1 H-imidazole 63 mg, and the yield is 25%.
         ​The structural formula thereof is as follows:
        
         1 ​H NMR delta 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, 3). 13 C NMR delta 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.
         ​Preparation of 5-methyl-4-phenyl-2-(thiophen-2-yl) -1 H-imidazole
         ​thiophene-2-formamidine hydrochloride is used for replacing formamidine acetate, the molar amount is not changed, and the
rest of the same is the light yellow solid product of 5-methyl-4-phenyl-2-(thiophen-2-yl) -1 H-imidazole 108 mg, and the yield is 45%.
         ​The structural formula thereof is as follows:
        
         1 ​H NMR delta 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, 3). 13 C NMR delta 140.85, 133.49, 132.71, 128.55, 127.70, 126.88, 126.64, 125.54, 124.02, 12.35. ​HRMS (ESI): m/z Calc for C 16 H 13 N 2 S [M
+ H] +: 241.0799, Found: 241.0799.

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