CN115260103A - Preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole - Google Patents
Preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole Download PDFInfo
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Abstract
The invention discloses a preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole. The method comprises the steps of carrying out high-area selective exchange on 2,4,5-trihalo-1- (difluoromethyl) -1H-imidazole and a dehalogenation reagent in an organic solvent under the atmosphere of inert gas to generate an intermediate state, and then reacting the intermediate state in the presence of water to generate 4,5-dihalo-1- (difluoromethyl) -1H-imidazole, wherein the dehalogenation reagent is selected from a Grignard reagent or an organic lithium reagent, the Grignard reagent is R-Mg-Br, the organic lithium reagent is R-Li, wherein R is C1-6 alkyl or phenyl, the molar ratio of the dehalogenation reagent to 2,4,5-trihalo-1- (difluoromethyl) -1H-imidazole is 1-1.5: 1. the preparation method can obtain the target compound with high selectivity and high yield, does not generate the isomer of the target compound, has simple subsequent separation and is beneficial to industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole.
Background
Researches show that the 1-position N atom of the imidazole derivative has substituent groups and the 4,5-dialkyl substituted imidazole derivative has good stability, and further, the hydrolysis stability and the thermal stability of the derivative are good when the 1-position N atom of the imidazole derivative is substituted by polyfluoromethyl. The difluoromethyl group has good metabolic stability and lipophilic property, so that the solubility or permeability of the compound can be improved, and the bioavailability and metabolic stability of the compound can be improved. Hydrogen in the difluoromethyl group has weak acidity, can form a hydrogen bond, and is beneficial to the combination of a medicament and a receptor so as to improve the activity of the medicament. The 1-N-difluoromethyl-4,5 disubstituted imidazole derivative is used as an important molecular building block for synthesizing a KRAS mutation inhibitor, and has important application value in developing therapeutic drugs for malignant tumors such as pancreatic cancer, colorectal cancer, lung cancer and the like; meanwhile, the fluorine-containing imidazole carbene can be used as a key material for preparing fluorine-containing imidazole carbene with high stability, and the fluorine-containing imidazole carbene is widely used as a complexing agent and a catalyst.
In the prior disclosed preparation method of 4,5-disubstituted-1- (difluoromethyl) -1H-imidazole, the difluoromethylation reaction of imidazole has poor selectivity and low yield. In addition, the large-scale production of 4,5-disubstituted-1- (difluoromethyl) -1H-imidazoles, which typically uses freon as the difluoromethylating agent, is environmentally hazardous.
For example, the difluoromethylation of 4,5-diphenyl-1H imidazole is disclosed in the foreign Journal of Russian Journal of Organic Chemistry, vol.46, no. 6, p.903-910, 2010, using chlorodifluoromethane as the fluoroalkylating agent, in an alkaline medium in the presence of a phase transfer catalyst at 30-40 ℃ with a product yield of only 37%.
For another example, WO2020085493A1 discloses a difluoromethylation reaction of 4,5-disubstituted-1H imidazole, which uses sodium difluorochloroacetate as a fluoroalkylation reagent, and the reaction is carried out in a microwave reactor at 150 ℃ for 16 hours with a product yield of only 11%.
Disclosure of Invention
The invention aims to solve the technical problems of the prior art and provide a preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole, which has high selectivity of target products and extremely high yield.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method of making 4,5-dihalo-1- (difluoromethyl) -1H-imidazole, said method of making comprising: reacting a compound of formula II
Reacting with a dehalogenation reagent in an organic solvent under an inert gas atmosphere to generate an intermediate state shown in a formula IV
And then reacting the intermediate state shown in the formula IV in the presence of water to generate the compound shown in the formula I
(ii) a The dehalogenation reagent is selected from a Grignard reagent or an organolithium reagent; the Grignard reagent is R-Mg-Br, the organolithium reagent is R-Li, wherein R is C1-6 alkyl or phenyl, in the formula I, the formula II and the formula IV, X is selected from Br or I, and the molar ratio of the Grignard reagent to the compound shown in the formula II is 1 to 1.5:1.
in some preferred embodiments, the dehalogenation reagent is a grignard reagent.
In some embodiments, the molar ratio of the dehalogenating agent to the compound of formula II is from 1 to 1.2:1.
in some embodiments, the grignard reagent is selected from a combination of one or more of methyl magnesium bromide, ethyl magnesium bromide, and phenyl magnesium bromide; the organolithium reagent is selected from the group consisting of methyl lithium, butyl lithium, sec-butyl lithium, iso-butyl lithium and tert-butyl lithium.
In some embodiments, in formula I, formula II, and formula IV, X is Br.
In some embodiments, the organic solvent is selected from one or a combination of two of tetrahydrofuran and diethyl ether.
In some embodiments, the volume-to-mass ratio of the organic solvent to the compound of formula II is 5 to 20ml:1g of the total weight of the composition.
In some embodiments, the dehalogenation reagent is a grignard reagent and the reaction to produce the intermediate of formula IV is at a temperature of from-5 to 5 ℃ for a time of from 1 to 2 hours.
In some embodiments, the dehalogenation reagent is an organolithium reagent and the reaction to produce the intermediate state of formula IV is at a temperature of-60 to-30 ℃ for 1 to 2 hours.
The temperature of the reaction in the present invention means a temperature measured by an external temperature control means of the reaction system, for example, a temperature measured in a water bath or a cooling device outside the reaction apparatus.
In some embodiments, the dehalogenation reagent is a grignard reagent, the compound represented by formula II is dissolved in the organic solvent under an inert gas atmosphere, the organic solvent is cooled to-5 to 5 ℃, the grignard reagent is added dropwise to the organic solvent, and the reaction is carried out at-5 to 5 ℃ for 1 to 2 hours.
In some embodiments, the dehalogenation reagent is an organolithium reagent, the compound represented by formula II is dissolved in the organic solvent under an inert gas atmosphere, the organic solvent is cooled to-60 to-30 ℃, the organolithium reagent is added dropwise into the organic solvent, and the reaction is carried out at-60 to-30 ℃ for 1 to 2 hours.
In some embodiments, the dehalogenation agent is a grignard reagent, the reaction temperature for generating the compound shown in the formula I is-5 ℃, and the reaction time is 10-30 minutes.
In some embodiments, the dehalogenation reagent is an organolithium reagent and the reaction to produce the compound of formula I is at a temperature of-5 to 5 ℃ for a time of 10 to 30 minutes. In some embodiments, the water is in large excess relative to the grignard reagent, while simultaneously acting as a post-treatment solvent.
In some embodiments, reacting the compound of formula IV in the presence of water to produce the compound of formula I is specifically: and adding water for reaction and layering to obtain an organic phase and a water phase, and drying, filtering, concentrating and carrying out column chromatography on the organic phase to obtain the compound shown in the formula I.
The inventors of the present invention have found that the regioselective exchange of a compound of formula II with a dehalogenating agent results in a specific intermediate state as shown in the following structure
And after water is added, the carbanion is combined with the proton in the water to finally form the compound shown in the formula I. And by controlling the molar ratio of the dehalogenation reagent to the compound shown in the formula II, one halogen substituent at a specific position of the compound shown in the formula II can be selectively substituted to generate the target compound shown in the formula I. The reaction has high regioselectivity, the yield of the target product is high, no isomer of the target product is generated, and the separation process of the target product is simple.
In some embodiments, the method of making further comprises a compound of formula III
And (3) carrying out a fluoro-alkylation reaction with a fluoro-alkylation reagent in a solvent under the alkaline condition to generate the compound shown in the formula II, wherein X is selected from Br or I, and the fluoro-alkylation reagent is selected from one or a combination of two of ethyl difluorobromoacetate and sodium difluorochloroacetate.
In some embodiments, in formula III, X is Br.
In some embodiments, the solvent is selected from one or a combination of two of tetrahydrofuran and acetonitrile.
In some embodiments, the volume-to-mass ratio of the solvent to the compound of formula III is 5 to 10ml:1g of the total weight of the composition.
In some embodiments, the fluoroalkylation reaction is at a temperature of 35 to 70 ℃ for a time of 12 to 18 hours.
In some embodiments, the basic conditions are formed by the addition of one or both bases selected from sodium hydroxide and potassium carbonate.
In some embodiments, the molar ratio of the base to the compound of formula III is 2 to 5:1.
in some embodiments, the molar ratio of the fluoroalkylating agent to the compound of formula III is from 1.2 to 3:1.
in some embodiments, the step of producing the compound of formula II comprises: dissolving the compound shown in the formula III in a solvent, adding alkali, heating to 35-70 ℃, adding the fluorinated alkylation reagent, and carrying out fluorinated alkylation reaction for 12-18 hours.
In some embodiments, the step of producing the compound of formula II further comprises: after the fluoroalkylation reaction is finished, cooling, concentrating, adding ice water and ethyl acetate for layering to obtain an organic phase and a water phase, washing, drying, filtering and concentrating the organic phase to obtain a crude product of the compound shown in the formula II, and recrystallizing to obtain the compound shown in the formula II.
The invention also provides a preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole, which comprises the following steps: under the inert gas atmosphere, the compound shown as the formula II
Dissolving in organic solvent, cooling the organic solvent to-5 ℃, dripping Grignard reagent into the organic solvent, reacting for 1-5 hours at-5 ℃, then adding water, and layering the system to obtain the compound containing the formula I
Then separating the organic phase from the aqueous phase to obtain the compound shown in the formula I; said formulaIn the formula I and the formula II, X is selected from Br or I, and the molar ratio of the Grignard reagent to the compound shown in the formula II is 1-1.5: 1.
the invention also provides a preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole, which comprises the following steps: under the inert gas atmosphere, the compound shown in the formula II
Dissolving in organic solvent, cooling the organic solvent to-60-30 ℃, dripping organic lithium reagent into the organic solvent, reacting for 1-5 hours at-60-30 ℃, then adding water, layering the system to obtain the compound containing the formula I
Then separating the organic phase from the aqueous phase to obtain the compound shown in the formula I; in the formula I and the formula II, X is selected from Br or I, and the molar ratio of the organic lithium reagent to the compound shown in the formula II is 1-1.5: 1.
the invention also provides 4,5-dihalo-1- (difluoromethyl) -1H-imidazole having the structural formula shown in formula I:
in the formula I, X is Br.
The present invention also provides a compound suitable for use in the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole, said compound having the structure shown in formula IV below:
；
wherein X is selected from Br or I, and Y is selected from MgBr or Li.
Preferably, X is Br.
Preferably, Y is MgBr.
Compared with the prior art, the invention has the following technical advantages:
1. the method comprises the steps of carrying out difluoromethylation reaction by using 2,4,5-trihalo-1H-imidazole as a substrate without generating selectivity problem, then adopting a dehalogenation reagent with a specific molar ratio to react with a compound shown in a formula II, and subsequently adding water to carry out further reaction, so that a target compound can be obtained with high selectivity and high yield, an isomer of the target compound cannot be generated, and the separation of the target product is simple. The present invention can achieve a yield of the target compound of 90% or more.
2. The invention avoids using Freon and other reagents with environmental hazard, and the synthetic route is green and environment-friendly.
3. The target compound obtained by the preparation method has high purity which can reach 97 percent and can be used as a synthetic intermediate of medicaments and fluorine-containing imidazole carbene.
4. The reaction and purification process of the invention is simple to operate, the reaction condition is mild and controllable, and the invention is beneficial to industrial production.
Drawings
FIG. 1 is a nuclear magnetic spectrum of 2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole prepared in example 1;
FIG. 2 is a nuclear magnetic spectrum of 4,5-dibromo-1- (difluoromethyl) -1H-imidazole prepared in example 1;
FIG. 3 is a mass spectrum of 4,5-dibromo-1- (difluoromethyl) -1H-imidazole prepared in example 1.
Detailed Description
The present invention is further described with reference to the following examples, which are not intended to limit the scope of the present invention.
Technical features of the embodiments described below may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described below are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The following examples are merely illustrative of several embodiments of the present invention, and the description thereof is more specific and detailed, but not to be construed as limiting the scope of the invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention. Therefore, the protection scope of the present patent should be subject to the appended claims.
Example 1
This example provides a method for preparing 4,5-dibromo-1- (difluoromethyl) -1H-imidazole:
step 1: preparation of 2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole
2,4,5-tribromo-1H-imidazole (50.0 g,164.1 mmol) was dissolved in acetonitrile (300 ml) and potassium carbonate (45.4 g,328.2 mmol) was added with stirring. The reaction was warmed to 50 ℃ and ethyl difluorobromoacetate (40.0 g,196.9 mmol) was slowly added to the reaction and stirred at 50 ℃ overnight. TLC spot plate reaction is complete, the reaction solution is cooled to room temperature, and the solvent is removed by concentration. Ice water (200 ml) and ethyl acetate (300 ml) were added, the layers were separated, the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to give crude, which was recrystallized to give 2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole 57.0 g as a white solid with 98% yield.
ESI-MS (m/z) of 2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole is 352.65[ m ] +H ]] + In CDCl 3 The hydrogen spectrum of Nuclear Magnetic Resonance (NMR) is shown in figure 1, and the specific values are as follows: 1 H NMR (400 MHz, CDCl 3 )：7.31 (s, 0.25H)，7.16 (s, 0.5H)，7.02 (s, 0.25H)。
and 2, step: preparation of 4,5-dibromo-1- (difluoromethyl) -1H-imidazole
2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole (20.0 g,56.4 mmol) was dissolved in tetrahydrofuran (400 mL) under nitrogen to give a reaction solution. After cooling to 0 ℃, ethyl magnesium bromide (1M, 56.4 mL,56.4 mmol) was slowly added dropwise to the reaction mixture, and the reaction was stirred for 1 hour. TLC spot plate reaction is complete. Water (400 mL) was added, and the mixture was stirred at 0 ℃ for 15 minutes, and the mixture was allowed to separate into layers, and the organic phase was collected. The aqueous layer was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography to afford 4,5-dibromo-1- (difluoromethyl) -1H-imidazole 14.4 g as a colorless oil in 93% yield and 97% purity.
4,5-Dibromo-1- (difluoromethyl) -1H-imidazole in CDCl 3 The hydrogen spectrum of Nuclear Magnetic Resonance (NMR) is shown in FIG. 2, and the specific values are as follows: 1 H NMR (400 MHz, CDCl 3 ): 7.89 (s, 1H), 7.20 (s, 0.26H), 7.05 (s, 0.52H), 6.90 (s, 0.26H). The mass spectrum of 4,5-dibromo-1- (difluoromethyl) -1H-imidazole is shown in FIG. 3, and the specific values are as follows: ESI-MS (m/z): 276.80 [ M + H +2 ]] + ，317.85 [M+H+MeCN+2]+。
Example 2
This example provides a process for large scale production of 4,5-dibromo-1- (difluoromethyl) -1H-imidazole:
step 1: preparation of 2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole
2,4,5-tribromo-1H-imidazole (2.00 kg,6.6 mol) was dissolved in acetonitrile (14L) and sodium hydroxide (528 g,13.2 mol) was added with stirring. The temperature was raised to 50 ℃ and ethyl difluorobromoacetate (2.68 kg,13.2 mol) was slowly added to the reaction system, followed by stirring at 50 ℃ overnight. TLC spot plate reaction is complete, the reaction solution is cooled to room temperature, and the solvent is removed by concentration. Ice water (10L) and ethyl acetate (10L) were added, layers were separated, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Crude recrystallization afforded 2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole 2.29 kg as a white solid in 98% yield.
And 2, step: preparation of 4,5-dibromo-1- (difluoromethyl) -1H-imidazole
2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole (1.70 kg,4.8 mol) was dissolved in anhydrous tetrahydrofuran (17L) solution under nitrogen and cooled to 0 ℃. Ethyl magnesium bromide (3M, 1.83L, 5.5 mol) was slowly added dropwise to the reaction solution, and the reaction was stirred for 1.5 hours. TLC spot plate reaction is complete. Water (17L) was added, and the mixture was stirred at 0 ℃ for 30 minutes, and the mixture was allowed to separate into layers, and the organic phase was collected. The aqueous layer was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was distilled under reduced pressure to give 4,5-dibromo-1- (difluoromethyl) -1H-imidazole 1.26 kg as a colorless oil in 95% yield and 97% purity.
Example 3
This example provides a method for preparing 4,5-dibromo-1- (difluoromethyl) -1H-imidazole: step 1 is the same as example 1, and step 2 is basically the same as example 1, except that: the ethyl magnesium bromide was replaced with the same molar amount of methyl magnesium bromide. The final 4,5-dibromo-1- (difluoromethyl) -1H-imidazole was in 95% yield and 96% purity.
Example 4
This example provides a method for preparing 4,5-dibromo-1- (difluoromethyl) -1H-imidazole: step 2 is the same as example 1, and step 1 is basically the same as example 1, except that: ethyl difluorobromoacetate was replaced with the same molar amount of sodium difluorochloroacetate. The final 4,5-dibromo-1- (difluoromethyl) -1H-imidazole was in 95% yield and 96% purity.
Example 5
This example provides a method for preparing 4,5-dibromo-1- (difluoromethyl) -1H-imidazole: step 1 as in example 1, step 2 was as follows:
2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole (20.0 g,56.4 mmol) was dissolved in tetrahydrofuran (400 ml) under nitrogen to give a reaction solution. After cooling to-60 ℃, tert-butyllithium (1.3M, 43.4 mL,56.4 mmol) was slowly added dropwise to the reaction mixture, and the reaction was stirred for 1 hour. TLC spot plate reaction is complete. Adding water (400 mL), stirring at 60 ℃ for 15 minutes, demixing the system, and collecting an organic phase. The aqueous layer was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography to give 4,5-dibromo-1- (difluoromethyl) -1H-imidazole 14.0g as a colorless oil in 90% yield and 95% purity.
Specific values of the hydrogen spectrum of nuclear magnetic resonance are as follows: 1 H NMR (400 MHz, CDCl 3 )：7.89 (s, 1H), 7.19 (s, 0.25H), 7.04 (s, 0.50H), 6.89 (s, 0.25H)。
example 6
This example provides a method for preparing 4,5-dibromo-1- (difluoromethyl) -1H-imidazole: step 1 as in example 1, and step 2 as follows:
2,4,5-tribromo-1- (difluoromethyl) -1H-imidazole (20.0 g,56.4 mmol) was dissolved in tetrahydrofuran (400 ml) under nitrogen to give a reaction solution. The reaction mixture was cooled to-60 ℃ and butyllithium (1.3M, 43.4 mL,56.4 mmol) was slowly added dropwise to the reaction mixture, followed by stirring for 1 hour. TLC spot plate reaction is complete. Adding water (400 mL), stirring at 60 ℃ for 15 minutes, demixing the system, and collecting an organic phase. The aqueous layer was extracted with ethyl acetate. The organic phase is dried by anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by column chromatography to give 4,5-dibromo-1- (difluoromethyl) -1H-imidazole 13.2g as a colorless oil in 85% yield and 95% purity.
Comparative example 1
This comparative example provides a preparation method: step 1 is the same as example 1, and step 2 is basically the same as example 1, except that: the amount of ethyl magnesium bromide was increased from 56.3 mmol to 112.6 mmol. As a result, it was found that 4,5-dibromo-1- (difluoromethyl) -1H-imidazole was not prepared, and 4-bromo-1- (difluoromethyl) -1H-imidazole was obtained.
Comparative example 2
This comparative example provides a preparation method: step 1 is the same as example 1, and step 2 is the same as example 1, and the difference is only that: the ethyl magnesium bromide was replaced with the same molar amount of sodium sulfite. As a result, it was found that the reaction yield was as low as 35%, the reaction was incomplete and a large amount of by-products were produced.
Comparative example 3
This comparative example provides a preparation method: step 1 is the same as example 1, and step 2 is the same as example 1, and the difference is only that: the ethyl magnesium bromide was replaced with the same molar amount of sodium borohydride. As a result, it was found that the reaction yield was as low as 40%, the reaction was incomplete and a large amount of by-products were produced.
Therefore, the Grignard reagent or the organic lithium reagent reacts with 2,4,5-trihalo-1- (difluoromethyl) -1H-imidazole at first, then water is added for removing reaction, and the Grignard reagent or the organic lithium reagent and the molar equivalent thereof are controlled, so that the halogen removal of 2,4,5-trihalo-1- (difluoromethyl) -1H-imidazole at a specific position can be realized, and a high-purity target product is obtained with high yield. The reagents of comparative examples 2 to 3 cannot be used for the synthesis of the target product of the present invention.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (15)
1. A preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole is characterized in that: the preparation method comprises the following steps: reacting a compound of formula II
Reacting with a dehalogenation reagent in an organic solvent under an inert gas atmosphere to generate an intermediate state shown in a formula IV
And then reacting the intermediate state shown in the formula IV in the presence of water to generate the compound shown in the formula I
(ii) a The dehalogenation reagent is selected from a Grignard reagent or an organic lithium reagent; the Grignard reagent is R-Mg-Br, the organic lithium reagent is R-Li, wherein R is C1-6 alkyl or phenyl; in the formula I, the formula II and the formula IV, X is selected from Br or I, and in the formula IV, Y is selected from MgBr or Li; the molar ratio of the Grignard reagent to the compound represented by the formula II is 1 to 1.5:1.
2. the process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 1 wherein: the dehalogenation reagent is a Grignard reagent; and/or the molar ratio of the dehalogenation reagent to the compound shown in the formula II is 1-1.2: 1; and/or, in the formula I, the formula II and the formula IV, X is Br.
3. The process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 1 wherein: the Grignard reagent is selected from one or more of methyl magnesium bromide, ethyl magnesium bromide and phenyl magnesium bromide; the organolithium reagent is selected from the group consisting of methyl lithium, butyl lithium, sec-butyl lithium, iso-butyl lithium and tert-butyl lithium.
4. The process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 1 wherein: the organic solvent is one or the combination of two of tetrahydrofuran and diethyl ether; and/or the volume mass ratio of the organic solvent to the compound shown in the formula II is 5-20 ml:1g; and/or, when the dehalogenation reagent is a Grignard reagent, the temperature of the reaction for generating the intermediate state shown in the formula IV is-5 ℃ and the time is 1-2 hours, and when the dehalogenation reagent is an organic lithium reagent, the temperature of the reaction for generating the intermediate state shown in the formula IV is-60-30 ℃ and the time is 1-2 hours.
5. The process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 1 wherein: when the dehalogenation reagent is a Grignard reagent, dissolving the compound shown in the formula II in the organic solvent under the atmosphere of inert gas, cooling the organic solvent to-5 ℃, dropwise adding the Grignard reagent into the organic solvent, and reacting for 1-2 hours at-5 ℃; when the dehalogenation reagent is an organic lithium reagent, dissolving the compound shown in the formula II in the organic solvent under the atmosphere of inert gas, cooling the organic solvent to-60 to-30 ℃, dropwise adding the organic lithium reagent into the organic solvent, and reacting for 1-2 hours at-60 to-30 ℃.
6. The process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 1 wherein: when the dehalogenation reagent is a Grignard reagent, the temperature of the reaction for generating the compound shown in the formula I is-5~5 ℃, and the time is 10-30 minutes, and when the dehalogenation reagent is an organic lithium reagent, the temperature of the reaction for generating the compound shown in the formula I is-60-30 ℃, and the time is 10-30 minutes; and/or, the intermediate state shown in the formula IV is reacted in the presence of water to generate the compound shown in the formula I: and adding water for reaction and layering to obtain an organic phase and a water phase, and drying, filtering, concentrating and carrying out column chromatography on the organic phase to obtain the compound shown in the formula I.
7. The process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 1 wherein: the preparation method also comprises the compound shown as the formula III
And (3) carrying out a fluoro-alkylation reaction with a fluoro-alkylation reagent in a solvent under the alkaline condition to generate the compound shown in the formula II, wherein X is selected from Br or I, and the fluoro-alkylation reagent is selected from one or a combination of two of ethyl difluorobromoacetate and sodium difluorochloroacetate.
8. The process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 7 wherein: the solvent is one or the combination of two of tetrahydrofuran and acetonitrile; and/or the volume mass ratio of the solvent to the compound shown in the formula III is 5-10 ml:1g of a compound; and/or the temperature of the fluoroalkylation reaction is 35-70 ℃ and the time is 12-18 hours.
9. The process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 7 wherein: the alkaline condition is formed by adding one or two bases selected from sodium hydroxide and potassium carbonate; and/or, in the formula III, X is Br.
10. The process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 9 wherein: the molar ratio of the base to the compound represented by the formula III is 2 to 5:1; and/or the molar ratio of the fluoroalkylating agent to the compound of formula III is 1.2 to 3:1.
11. the process for the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole according to claim 7 wherein: the step of producing the compound represented by formula II comprises: dissolving the compound shown in the formula III in a solvent, adding alkali, heating to 35-70 ℃, adding the fluorinated alkylation reagent, and carrying out fluorinated alkylation reaction for 12-18 hours.
12. A preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole is characterized in that: the preparation method comprises the following steps: under the inert gas atmosphere, the compound shown in the formula II
Dissolving in organic solvent, cooling the organic solvent to-5 ℃, dripping Grignard reagent into the organic solvent, reacting for 1-5 hours at-5 ℃, then adding water, and layering the system to obtain the compound containing the formula I
Then separating the organic phase from the aqueous phase to obtain the compound shown in the formula I; in the formula I and the formula II, X is selected from Br or I, and the molar ratio of the Grignard reagent to the compound shown in the formula II is 1-1.5: 1.
13. a preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole is characterized in that: the preparation method comprises the following steps: under the inert gas atmosphere, the compound shown in the formula II
Dissolving in organic solvent, cooling the organic solvent to-60-30 ℃, dripping organic lithium reagent into the organic solvent, reacting for 1-5 hours at-60-30 ℃, then adding water, layering the system to obtain the compound containing the formula I
And an aqueous phase, after which the organic phase is separatedObtaining a compound shown as a formula I; in the formula I and the formula II, X is selected from Br or I, and the molar ratio of the organic lithium reagent to the compound shown in the formula II is 1-1.5: 1.
14. a 4,5-dihalo-1- (difluoromethyl) -1H-imidazole characterized by: it has the structural formula shown in formula I:
in the formula I, X is Br.
15. A compound suitable for use in the preparation of 4,5-dihalo-1- (difluoromethyl) -1H-imidazole characterized by: the compound has the structure shown in formula IV:
wherein, X is selected from Br or I, and Y is selected from MgBr or Li.
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