CN115093372B - Synthesis method of imidazole derivative - Google Patents
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Abstract
The invention relates to a synthesis method of imidazole derivatives, which comprises the following steps: mixing aurone or its derivative I, benzamidine or its derivative II, iodine and alkali, adding solvent, and heating to react; after the reaction is finished, cooling to room temperature, washing, extracting, drying and concentrating the reaction liquid under reduced pressure, and separating by chromatography to obtain the imidazole derivative III. The raw materials used in the invention are conventional, cheap and easily available, and the accelerator iodine is cheap, safe and nontoxic; the domino reaction strategy is utilized to improve the reaction efficiency and reduce the separation and purification operation; good reaction selectivity, less side reaction and high product yield; the spiro ring opening strategy is utilized to realize the synthesis of imidazole derivatives with conjugated structures, so that a large amount of chemical oxidants are avoided, and the pollution is small; can effectively solve the problems of difficult or expensive raw material synthesis, high catalyst toxicity, high oxidant demand, harsh reaction conditions, poor selectivity, complex product separation and low yield existing in the existing imidazole derivative synthesis method.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of an imidazole derivative.
Background
Imidazole is an important five-membered nitrogen-containing heterocyclic compound, and the skeleton of the imidazole is widely existing in natural products and drug molecules and shows remarkable biological activity. Imidazole derivatives are also important organic synthesis intermediates of medicines, pesticides, dyes and the like, and are widely applied to the fields of ionic liquids, proton exchange materials, organic luminescent materials and the like.
In view of this, a great deal of research has been conducted on the synthesis of imidazole derivatives, and the following synthetic methods have been developed: (1) The Debus synthesis method is characterized in that alpha-diketone, aldehyde and ammonia are used as raw materials to perform condensation reaction, and imidazole derivatives are generated by ring closure; (2) An alpha-aminoacetal method, which utilizes a cyclization reaction of an alpha-aminoacetal and an amide to form an imidazole derivative; (3) Synthesizing ethylenediamine, and reacting substituted ethylenediamine with carboxylic acid, ester or anhydride to obtain imidazole derivative; (4) The acetonitrile method is to generate imidazole products by utilizing the reaction of 3-bromo-2-acetonitrile methyl ester and primary amine under the action of alkaline reagent; (5) An imidazoline oxidation method for oxidizing imidazoline into an imidazole derivative having a conjugated structure by using a large amount of an oxidizing agent; (6) In the Claisen rearrangement reaction method, in the reaction between amidoxime and propiolate, water molecules are removed by the Claisen rearrangement reaction to form an imidazole ring compound.
Although these methods all allow the synthesis of a wide variety of imidazole derivatives, there are several disadvantages: for example, the Debus synthesis method has more byproducts, lower product yield and more troublesome product separation and purification; the other methods also have the problems of difficult or expensive raw material synthesis, high catalyst toxicity, need of using a large amount of oxidizing agents, harsh reaction conditions, poor reaction selectivity, complicated product separation and purification, low yield and the like.
Disclosure of Invention
The invention aims to provide a synthesis method of imidazole derivatives, which can effectively solve the problems of difficult or expensive synthesis of raw materials, high catalyst toxicity, high oxidant demand, harsh reaction conditions, poor selectivity, complex product separation and low yield of the existing synthesis method of imidazole derivatives.
In order to solve the technical problems, the invention adopts the following technical scheme:
a synthesis method of imidazole derivatives has the following reaction general formula:
wherein: r is R 1 Is aryl, alkyl or heterocyclyl; r is R 2 Is aryl or alkyl; r is R 3 Is aryl, benzyl or alkyl.
The synthesis method of the imidazole derivative comprises the following steps:
(a) Mixing aurone or its derivative I, benzamidine or its derivative II, iodine and alkali, adding solvent, and heating to react;
(b) After the reaction is finished, cooling to room temperature, washing, extracting, drying and concentrating the reaction liquid under reduced pressure, and separating by chromatography to obtain the imidazole derivative III.
Wherein, the ratio of the amount of the substances of the orange ketone or the derivative thereof, the benzamidine or the derivative thereof, the iodine and the alkali in the step (a) is 1:1.2-1.8:1-1.5:1; the base is sodium acetate, potassium carbonate, sodium hydroxide, sodium ethoxide, triethylamine, 4-dimethylaminopyridine or 1, 8-diazabicyclo [5.4.0] undec-7-ene; the solvent is 1, 2-dichloroethane, acetonitrile, toluene, chlorobenzene, 1, 4-dioxane, dimethyl sulfoxide or N, N-dimethylformamide, and the volume of the solvent is 10-12 times of the total mass of the raw materials.
The reaction temperature in the step (a) is 80-130 ℃ and the reaction time is 5-10 h.
Wherein the solution adopted in the washing step in the step (b) is sodium thiosulfate aqueous solution; the extractant adopted in the extraction step is ethyl acetate; the drying step is to dry with anhydrous sodium sulfate; the chromatographic conditions of the chromatographic separation step are as follows: the 200-300 mesh silica gel column, the eluent is a mixture of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1:6-10.
When R is 1 Is phenyl, R 2 Is phenyl, R 3 When benzyl, the synthesis mechanism of the imidazole derivative is as follows:
according to the synthesis method of the imidazole derivative, firstly, the aurone I and the N-phenyl benzamidine II undergo an aza-Michael addition reaction under the induction of iodine to obtain a ketone intermediate A, the ketone intermediate A can be converted into an enol intermediate B, the enol intermediate A and the iodine undergo a substitution reaction to generate a spiro intermediate D through intramolecular nucleophilic substitution reaction, the spiro intermediate D undergoes an E2-like elimination reaction under the action of alkali 4-dimethylaminopyridine to form an oxyanion intermediate E, and a molecule of proton is then extracted by the E to generate a final target product III.
Compared with the prior art, the technical scheme of the invention has the following beneficial effects: the adopted raw materials are conventional, cheap and easily available, and are suitable for substrates substituted by various functional groups; the adopted accelerator iodine is a cheap, safe and nontoxic reagent; the domino reaction strategy is utilized to greatly improve the reaction efficiency, reduce the separation and purification operation and simultaneously reduce the cost; the reaction selectivity is good, the side reaction is less, the product yield is high, and the obtained product is a single imidazole derivative; the spiro ring opening strategy is utilized to realize the synthesis of imidazole derivatives with conjugated structures, so that the atom utilization rate is high, a large amount of chemical oxidants can be avoided, and the pollution is small. The comprehensive problems of the method in the background technology are effectively solved.
Drawings
FIG. 1 is a schematic diagram of the target product of example 1 1 H NMR spectrum;
FIG. 2 is a schematic diagram of the target product of example 1 13 C NMR spectrum;
FIG. 3 is a schematic diagram of the target product of example 2 1 H NMR spectrum;
FIG. 4 is a schematic diagram of the target product of example 2 13 C NMR spectrum;
FIG. 5 is a schematic diagram of the target product of example 3 1 H NMR spectrum;
FIG. 6 is a diagram of the target product of example 3 13 C NMR spectrum;
FIG. 7 is a schematic diagram of the target product of example 4 1 H NMR spectrum;
FIG. 8 is a schematic diagram of the target product of example 4 13 C NMR spectrum;
FIG. 9 is a schematic diagram of the target product of example 5 1 H NMR spectrum;
FIG. 10 is a schematic diagram of the target product of example 5 13 C NMR spectrum;
FIG. 11 is a diagram of the target product of example 6 1 H NMR spectrum;
FIG. 12 is a sample of the target product of example 6 13 C NMR spectrum;
FIG. 13 is a sample of the target product of example 7 1 H NMR spectrum;
FIG. 14 is a schematic representation of the target product of example 7 13 C NMR spectrum;
FIG. 15 shows the target product of example 8 1 H NMR spectrum;
FIG. 16 is a sample of the target product of example 8 13 C NMR spectrum.
Detailed Description
The present invention will be specifically described with reference to examples below in order to make the objects and advantages of the present invention more apparent. It should be understood that the following text is intended to describe only one or more specific embodiments of the invention and does not limit the scope of the invention strictly as claimed.
Example 1
A synthesis method of 1-benzyl-2, 4-diphenyl-5-o-hydroxybenzoyl-1H-imidazole comprises the following steps:
to a 25mL reaction tube were added 44.4mg (0.2 mmol) of 2-benzylidenebenzofuran-3 (2H) -one, 63.0mg (0.3 mmol) of N-benzylbenzamidine, 50.8mg (0.2 mmol) of iodine, 24.4mg (0.2 mmol) of 4-dimethylaminopyridine and 2mL of chlorobenzene, stirred at 110℃for 6 hours, cooled to room temperature after the reaction, washed with 10mL of sodium thiosulfate solution, and extracted three times with 20mL of ethyl acetate, and the separated organic phase was dried over anhydrous sodium sulfate and separated by silica gel column chromatography (V ethyl acetate: V petroleum ether=1:6) to give 75.1mg of the target product in 87% yield as a yellow solid.
The nuclear magnetic resonance spectrum of the target product is shown in fig. 1 and 2: 1 H NMR(600MHz,CDCl 3 )δ11.75(s,1H),7.70–7.66(m,2H),7.50–7.47(m,3H),7.46(d,J＝7.5Hz,2H),7.22–7.12(m,7H),7.08(t,J＝7.4Hz,1H),6.93(d,J＝7.6Hz,2H),6.84(d,J＝8.3Hz,1H),6.33(t,J＝7.6Hz,1H),5.50(s,2H)； 13 C NMR(125MHz,CDCl 3 )δ193.0,162.7,152.0,147.1,136.8,136.5,133.4,133.3,130.0,129.7,129.6(2C),129.0(2C),128.9(2C),128.8(2C),128.3(2C),128.0,127.9,126.6(2C),125.7,119.6,118.7,117.6,49.4；HRMS(ESI-TOF)calcd for C 29 H 23 N 2 O 2 [M+H] + 431.1760,found 431.1766。
wherein the chemical structural formula of the 1-benzyl-2, 4-diphenyl-5-o-hydroxybenzoyl-1H-imidazole is as follows:
the mechanism of synthesis of the imidazole derivative of this example is as follows:
firstly, aurone I and N-phenyl benzamidine II undergo aza-Michael addition reaction under the induction of iodine to obtain a ketone intermediate A, the ketone intermediate A can be converted into an enol intermediate B, the enol intermediate A and iodine undergo substitution reaction to generate an intermediate C, the intermediate C undergoes intramolecular nucleophilic substitution reaction to generate a spiro intermediate D, the spiro intermediate D undergoes similar E2 type elimination reaction under the action of alkali 4-dimethylaminopyridine to form an oxyanion intermediate E, and one molecule of proton is then extracted by E to generate a final target product III.
Example 2
A synthesis method of 1-benzyl-2-phenyl-4-p-tolyl-5-o-hydroxybenzoyl-1H-imidazole comprises the following steps:
to a 25mL reaction tube was added 47.2mg (0.2 mmol) of 2- (4-methylbenzylidene) benzofuran-3 (2H) -one, 63.0mg (0.3 mmol) of N-benzylbenzamidine, 50.8mg (0.2 mmol) of iodine, 24.4mg (0.2 mmol) of 4-dimethylaminopyridine and 2mL of chlorobenzene, and the mixture was stirred at 110℃for 6 hours, cooled to room temperature after the completion of the reaction, washed with 10mL of sodium thiosulfate solution, and then extracted three times with 20mL of ethyl acetate, and the separated organic phase was dried over anhydrous sodium sulfate and separated by column chromatography on silica gel (V ethyl acetate: V petroleum ether=1:6) to give 73.8mg of the objective product in 83% yield as a yellow solid.
The nuclear magnetic resonance spectrum of the target product is shown in fig. 3 and 4: 1 H NMR(500MHz,CDCl 3 )δ11.83(s,1H),7.70–7.65(m,2H),7.50–7.45(m,3H),7.35(d,J＝8.1Hz,2H),7.23–7.19(m,2H),7.13(t,J＝7.4Hz,2H),7.07(t,J＝7.3Hz,1H),6.96(d,J＝7.9Hz,2H),6.93(d,J＝7.3Hz,2H),6.84(d,J＝8.7Hz,1H),6.35(t,J＝7.6Hz,1H),5.49(s,2H),2.23(s,3H)； 13 C NMR(125MHz,CDCl 3 )δ193.1,162.6,151.9,147.1,137.8,136.8,136.4,133.4,130.3,129.9,129.7,129.6(2C),129.0(2C),128.9(2C),128.8(4C),127.8,126.6(2C),125.3,119.5,118.7,117.6,49.3,21.3；HRMS(ESI-TOF)calcd for C 30 H 25 N 2 O 2 [M+H] + 445.1916,found 445.1925。
wherein the chemical structural formula of the 1-benzyl-2-phenyl-4-p-tolyl-5-o-hydroxybenzoyl-1H-imidazole is as follows:
example 3
The synthesis method of the 1-benzyl-4-o-chlorophenyl-2-phenyl-5-o-hydroxybenzoyl-1H-imidazole comprises the following steps:
to a 25mL reaction tube were added 51.4mg (0.2 mmol) of 2- (2-chlorobenzenemethylene) benzofuran-3 (2H) -one, 63.0mg (0.3 mmol) of N-benzylbenzamidine, 50.8mg (0.2 mmol) of iodine, 24.4mg (0.2 mmol) of 4-dimethylaminopyridine and 2mL of chlorobenzene, stirred at 110℃for 6 hours, cooled to room temperature after the reaction, washed with 10mL of sodium thiosulfate solution, and extracted three times with 20mL of ethyl acetate, and the separated organic phase was dried over anhydrous sodium sulfate and separated by silica gel column chromatography (VATE: VATIVER=1:6) to give 74.6mg of the desired product in 80% yield as a yellow solid.
The nuclear magnetic resonance spectrum of the target product is shown in fig. 5 and 6: 1 H NMR(500MHz,CDCl 3 )δ11.43(s,1H),7.71–7.66(m,2H),7.56(d,J＝7.6Hz,1H),7.50–7.44(m,3H),7.23–7.17(m,3H),7.17–7.12(m,4H),7.11–7.06(m,1H),6.98(d,J＝7.4Hz,2H),6.80(d,J＝8.7Hz,1H),6.30(t,J＝7.6Hz,1H),5.64(s,2H)； 13 C NMR(125MHz,CDCl 3 )δ191.6,162.0,152.3,145.3,137.1,136.1,133.6,133.3,132.9,132.1,130.1,129.64,129.60(2C),129.5,129.4,128.93(2C),128.90(2C),127.8,127.3,126.8,126.3(2C),119.7,118.0,117.4,49.4；HRMS(ESI-TOF)calcd for C 29 H 22 ClN 2 O 2 [M+H] + 465.1370,found 465.1369。
wherein the chemical structural formula of the 1-benzyl-4-o-chlorophenyl-2-phenyl-5-o-hydroxybenzoyl-1H-imidazole is as follows:
example 4
A synthesis method of 1-benzyl-4- (2-furyl) -2-phenyl-5-o-hydroxybenzoyl-1H-imidazole comprises the following steps:
to a 25mL reaction tube were added 42.4mg (0.2 mmol) of 2- (2-furanmethylene) benzofuran-3 (2H) -one, 63.0mg (0.3 mmol) of N-benzyl benzamidine, 50.8mg (0.2 mmol) of iodine, 24.4mg (0.2 mmol) of 4-dimethylaminopyridine and 2mL of chlorobenzene, and the mixture was stirred at 110℃for 6 hours, cooled to room temperature after the reaction was completed, washed with 10mL of sodium thiosulfate solution, and then extracted three times with 20mL of ethyl acetate, and the separated organic phase was dried over anhydrous sodium sulfate and separated by silica gel column chromatography (V ethyl acetate: V petroleum ether=1:6) to give 60.7mg of the objective product in 72% yield as a yellow solid.
The nuclear magnetic resonance spectrum of the target product is shown in fig. 7 and 8: 1 H NMR(500MHz,CDCl 3 )δ11.71(s,1H),7.68–7.64(m,2H),7.50–7.46(m,3H),7.35–7.30(m,2H),7.14–7.10(m,3H),7.07(t,J＝7.3Hz,1H),6.93–6.88(m,3H),6.59–6.53(m,2H),6.28(dd,J＝3.3,1.8Hz,1H),5.43(s,2H)； 13 C NMR(125MHz,CDCl 3 )δ192.5,162.6,152.2,147.9,142.7,137.3,136.53,136.52,133.0,130.1,129.7(2C),129.5,129.0(2C),128.8(2C),128.0,126.7(2C),125.1,120.4,118.8,117.8,111.4,109.3,49.5；HRMS(ESI-TOF)calcd for C 27 H 21 N 2 O 3 [M+H] + 421.1552,found 421.1556。
wherein the chemical structural formula of the 1-benzyl-4- (2-furyl) -2-phenyl-5-o-hydroxybenzoyl-1H-imidazole is as follows:
example 5
The synthesis method of 1-benzyl-4-phenyl-2-m-tolyl-5-o-hydroxybenzoyl-1H-imidazole comprises the following steps:
to a 25mL reaction tube was added 44.4mg (0.2 mmol) of 2-benzylidenebenzofuran-3 (2H) -one, 67.2mg (0.3 mmol) of N-benzyl-3-methylbenzamidine, 50.8mg (0.2 mmol) of iodine, 24.4mg (0.2 mmol) of 4-dimethylaminopyridine and 2mL of chlorobenzene, stirred at 110℃for 6 hours, cooled to room temperature after the reaction, washed with 10mL of sodium thiosulfate solution, and extracted three times with 20mL of ethyl acetate, and the separated organic phase was dried over anhydrous sodium sulfate and separated by silica gel column chromatography (VATE: VATE=1:6) to give 74.5mg of the target product in 84% yield as a yellow solid.
The nuclear magnetic resonance spectrum of the target product is shown in fig. 9 and 10: 1 H NMR(500MHz,CDCl 3 )δ11.79(s,1H),7.54(s,1H),7.48–7.42(m,3H),7.35(t,J＝7.6Hz,1H),7.29(d,J＝7.6Hz,1H),7.22–7.12(m,7H),7.08(t,J＝7.3Hz,1H),6.94(d,J＝7.4Hz,2H),6.83(d,J＝8.3Hz,1H),6.32(t,J＝7.6Hz,1H),5.51(s,2H),2.40(s,3H)； 13 C NMR(125MHz,CDCl 3 )δ192.9,162.6,152.2,147.1,138.8,136.9,136.5,133.4,133.3,130.8,130.5,129.5,128.9(2C),128.8(2C),128.7,128.3(2C),128.0,127.8,126.6(2C),126.4,125.6,119.5,118.6,117.6,49.4,21.5；HRMS(ESI-TOF)calcd for C 30 H 25 N 2 O 2 [M+H] + 445.1916,found 445.1924。
wherein the chemical structural formula of the 1-benzyl-4-phenyl-2-m-tolyl-5-o-hydroxybenzoyl-1H-imidazole is as follows:
example 6
A synthesis method of 1-phenethyl-2, 4-diphenyl-5-o-hydroxybenzoyl-1H-imidazole comprises the following steps:
to a 25mL reaction tube were added 44.4mg (0.2 mmol) of 2-benzylidenebenzofuran-3 (2H) -one, 67.2mg (0.3 mmol) of N-phenethylbenzamidine, 50.8mg (0.2 mmol) of iodine, 24.4mg (0.2 mmol) of 4-dimethylaminopyridine and 2mL of chlorobenzene, stirred at 110℃for 6 hours, cooled to room temperature after the reaction, washed with 10mL of sodium thiosulfate solution, and extracted three times with 20mL of ethyl acetate, and the separated organic phase was dried over anhydrous sodium sulfate and separated by silica gel column chromatography (V ethyl acetate: V petroleum ether=1:6) to give 78.3mg of the objective product in 88% yield as a yellow solid.
Nuclear magnetic resonance spectra of the target product are shown in fig. 11 and 12: 1 H NMR(500MHz,CDCl 3 )δ12.03(s,1H),7.53–7.50(m,2H),7.50–7.46(m,3H),7.44–7.40(m,2H),7.34–7.27(m,2H),7.19–7.10(m,6H),6.96(d,J＝8.1Hz,1H),6.92–6.88(m,2H),6.42(t,J＝7.6Hz,1H),4.52(t,J＝7.4Hz,2H),2.85(t,J＝7.4Hz,2H)； 13 C NMR(125MHz,CDCl 3 )δ192.8,162.9,151.8,147.6,137.1,136.7,133.7,133.6,130.0,129.8,129.5(2C),129.2(2C),128.81(2C),128.76(2C),128.7(2C),128.3(2C),128.0,127.0,125.4,119.7,118.8,117.9,47.2,37.7；HRMS(ESI-TOF)calcd for C 30 H 25 N 2 O 2 [M+H] + 445.1916,found 445.1919。
wherein the chemical structural formula of the 1-phenethyl-2, 4-diphenyl-5-o-hydroxybenzoyl-1H-imidazole is as follows:
example 7
A synthesis method of 1,2, 4-triphenyl-5-o-hydroxybenzoyl-1H-imidazole comprises the following steps:
to a 25mL reaction tube were added 44.4mg (0.2 mmol) of 2-benzylidenebenzofuran-3 (2H) -one, 58.8mg (0.3 mmol) of N-phenylbenzamidine, 50.8mg (0.2 mmol) of iodine, 24.4mg (0.2 mmol) of 4-dimethylaminopyridine and 2mL of chlorobenzene, stirred at 110℃for 6 hours, cooled to room temperature after the reaction was completed, washed with 10mL of sodium thiosulfate solution, and then extracted three times with 20mL of ethyl acetate, and the separated organic phase was dried over anhydrous sodium sulfate and separated by silica gel column chromatography (V ethyl acetate: V petroleum ether=1:6) to give 72.6mg of the target product in the form of 87% yield as a yellow solid.
Nuclear magnetic resonance spectra of the target product are shown in fig. 13 and 14: 1 H NMR(500MHz,CDCl 3 )δ11.67(s,1H),7.57–7.53(m,2H),7.49(dd,J＝8.0,1.6Hz,1H),7.46–7.43(m,2H),7.40–7.35(m,3H),7.34–7.26(m,4H),7.25–7.18(m,5H),6.89(d,J＝8.4Hz,1H),6.51(t,J＝7.6Hz,1H)； 13 C NMR(125MHz,CDCl 3 )δ192.6,162.7,149.8,145.6,136.9,136.8,133.4,133.1,129.5(2C),129.4,129.3,129.2(2C),129.1,128.7(2C),128.45(2C),128.39(2C),128.1,127.7(3C),120.3,119.0,117.9；HRMS(ESI-TOF)calcd for C 28 H 21 N 2 O 2 [M+H] + 417.1603,found 417.1611。
wherein the chemical structural formula of the 1,2, 4-triphenyl-5-o-hydroxybenzoyl-1H-imidazole is as follows:
example 8
A synthesis method of 1-p-methoxyphenyl-2, 4-diphenyl-5-o-hydroxybenzoyl-1H-imidazole comprises the following steps:
to a 25mL reaction tube were added 44.4mg (0.2 mmol) of 2-benzylidenebenzofuran-3 (2H) -one, 67.8mg (0.3 mmol) of N-p-methoxyphenyl benzamidine, 50.8mg (0.2 mmol) of iodine, 24.4mg (0.2 mmol) of 4-dimethylaminopyridine and 2mL of chlorobenzene, and the mixture was stirred at 110℃for 6 hours, cooled to room temperature after the reaction, washed with 10mL of sodium thiosulfate solution, and then extracted three times with 20mL of ethyl acetate, and the separated organic phase was dried over anhydrous sodium sulfate and separated by silica gel column chromatography (V ethyl acetate: V petroleum ether=1:6) to give 76.9mg of the target product in 86% yield as a yellow solid.
Nuclear magnetic resonance spectra of the target product are shown in fig. 15 and 16: 1 H NMR(500MHz,CDCl 3 )δ11.73(s,1H),7.56–7.53(m,2H),7.50–7.46(m,3H),7.34–7.26(m,4H),7.24–7.14(m,5H),6.89(d,J＝8.4Hz,1H),6.86(d,J＝8.9Hz,2H),6.51(t,J＝7.6Hz,1H),3.81(s,3H)； 13 C NMR(125MHz,CDCl 3 )δ192.7,162.7,159.7,150.0,145.4,136.9,133.4,133.2,129.5,129.4,129.23,129.17(2C),128.8(2C),128.7(2C),128.44(2C),128.41(2C),128.1,127.8,120.2,119.0,117.9,114.6(2C),55.5；HRMS(ESI-TOF)calcd for C 29 H 23 N 2 O 3 [M+H] + 447.1709,found 447.1713。
wherein the chemical structural formula of the 1-p-methoxyphenyl-2, 4-diphenyl-5-o-hydroxybenzoyl-1H-imidazole is as follows:
while the embodiments of the present invention have been described in detail with reference to the examples, the present invention is not limited to the above embodiments, and it will be apparent to those skilled in the art that various equivalent changes and substitutions can be made therein without departing from the principles of the present invention, and such equivalent changes and substitutions should also be considered to be within the scope of the present invention.
Claims (6)
1. The synthesis method of the imidazole derivative is characterized by comprising the following reaction general formula:
wherein: r is R 1 Phenyl, p-tolyl, o-chlorophenyl or 2-furyl; r is R 2 Is phenyl or m-tolyl; r is R 3 Is benzyl, phenethyl, phenyl or p-methoxyphenyl;
the method specifically comprises the following steps:
(a) Mixing aurone or its derivative I, benzamidine or its derivative II, iodine and alkali, adding solvent, and heating to react; wherein, the alkali is 4-dimethylaminopyridine, and the solvent is chlorobenzene;
(b) After the reaction is finished, cooling to room temperature, washing, extracting, drying and concentrating the reaction liquid under reduced pressure, and separating by chromatography to obtain the imidazole derivative III.
2. The method for synthesizing an imidazole derivative according to claim 1, wherein: the ratio of the amount of the substances of the aurone or the derivative thereof, the benzamidine or the derivative thereof, the iodine and the alkali in the step (a) is 1:1.2-1.8:1-1.5:1.
3. The method for synthesizing an imidazole derivative according to claim 1, wherein: the volume of the solvent is 10-12 times of the total mass of the raw materials.
4. The method for synthesizing an imidazole derivative according to claim 1, wherein: the reaction temperature in the step (a) is 80-130 ℃ and the reaction time is 5-10 h.
5. The method for synthesizing an imidazole derivative according to claim 1, wherein: the solution adopted in the washing step in the step (b) is sodium thiosulfate aqueous solution; the extractant adopted in the extraction step is ethyl acetate; the drying step is drying using anhydrous sodium sulfate.
6. The method for synthesizing an imidazole derivative according to claim 1, wherein the chromatographic conditions in the chromatographic separation step in the step (b) are: the 200-300 mesh silica gel column, the eluent is a mixture of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1:6-10.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1088581A (en) * | 1992-07-17 | 1994-06-29 | 史密丝克莱恩比彻姆公司 | Endothelin-receptor antagonists |
| CA2156121A1 (en) * | 1994-09-05 | 1996-03-06 | Tsuyoshi Tomiyama | Method of manufacturing the cycloheptimidazole derivatives |
| CN102365280A (en) * | 2009-01-26 | 2012-02-29 | 多曼治疗学公司 | New adenosine receptor ligands and uses thereof |
| CN104177298A (en) * | 2014-09-18 | 2014-12-03 | 湘潭大学 | 4, 4-disubstituted-4, 5-dihydro-1H-imidazole-5-one and derivatives thereof as well as synthesis method thereof |
| CN104844518A (en) * | 2015-04-08 | 2015-08-19 | 浙江大学 | Preparation method of 2,4,5-trisubstituted imidazole compound |
| CN105001163A (en) * | 2015-07-20 | 2015-10-28 | 西北大学 | Tetra-substituted imidazole synthesis method |
| CN106349147A (en) * | 2016-08-30 | 2017-01-25 | 南阳师范学院 | Synthetic method of pyrrole derivatives |
| CN108976170A (en) * | 2018-08-14 | 2018-12-11 | 华南理工大学 | A kind of 5- trifluoromethyl -4H- imidazoline -4- ketone derivatives and synthetic method |
| CN115028564A (en) * | 2022-07-01 | 2022-09-09 | 安徽工程大学 | Synthetic method of pyrrole derivative |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104245781B (en) * | 2012-02-20 | 2018-09-21 | 巴斯夫欧洲公司 | The antimicrobial acivity of biocide is improved with polymer |
| WO2018204764A1 (en) * | 2017-05-05 | 2018-11-08 | Camp4 Therapeutics Corporation | Identification and targeted modulation of gene signaling networks |
-
2022
- 2022-06-16 CN CN202210679449.XA patent/CN115093372B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1088581A (en) * | 1992-07-17 | 1994-06-29 | 史密丝克莱恩比彻姆公司 | Endothelin-receptor antagonists |
| CA2156121A1 (en) * | 1994-09-05 | 1996-03-06 | Tsuyoshi Tomiyama | Method of manufacturing the cycloheptimidazole derivatives |
| CN102365280A (en) * | 2009-01-26 | 2012-02-29 | 多曼治疗学公司 | New adenosine receptor ligands and uses thereof |
| CN104177298A (en) * | 2014-09-18 | 2014-12-03 | 湘潭大学 | 4, 4-disubstituted-4, 5-dihydro-1H-imidazole-5-one and derivatives thereof as well as synthesis method thereof |
| CN104844518A (en) * | 2015-04-08 | 2015-08-19 | 浙江大学 | Preparation method of 2,4,5-trisubstituted imidazole compound |
| CN105001163A (en) * | 2015-07-20 | 2015-10-28 | 西北大学 | Tetra-substituted imidazole synthesis method |
| CN106349147A (en) * | 2016-08-30 | 2017-01-25 | 南阳师范学院 | Synthetic method of pyrrole derivatives |
| CN108976170A (en) * | 2018-08-14 | 2018-12-11 | 华南理工大学 | A kind of 5- trifluoromethyl -4H- imidazoline -4- ketone derivatives and synthetic method |
| CN115028564A (en) * | 2022-07-01 | 2022-09-09 | 安徽工程大学 | Synthetic method of pyrrole derivative |
Non-Patent Citations (5)
| Title |
|---|
| Copper(I)-Mediated Cascade Reactions: An Efficient Approach to the Synthesis of Functionalized Benzofuro[3,2-d]pyrimidines;Bo Chao，等;ORGANIC LETTERS;第14卷(第09期);第2398-2401页 * |
| Cytotoxic activity of 5-benzoylimidazole and related compounds against human oral tumor cell lines;KUNIKO TERASAWA，等;ANTICANCER RESEARCH;第21卷(第2A期);第1081-1086页 * |
| Synthesis of Fully Substituted 5-(o-Hydroxybenzoyl)imidazoles via Iodine-Promoted Domino Reaction of Aurones with Amidines;Hui Xu，等;JOURNAL OF ORGANIC CHEMISTRY;第87卷(第24期);第16204-16212页 * |
| 元英进，等.制药工艺学.化学工业出版社,2007,第39页. * |
| 环丙烷与不饱和化合物发生[3+2]扩环反应的研究进展;刘文竹，等;有机化学;第40卷(第05期);第1150-1176页 * |
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