A process for the synthesis of 4-chloro-2-cyano-5-p-tolyl-1H-imidazole

Abstract

The application provides a synthesis method of 4-chloro-2-cyano-5-p-tolyl-1 H Imidazole, and belongs to the field of synthesis of medical intermediates. The method uses toluene and dichloropropionitrile as raw materials, and firstly obtains 1-p-tolyl-2,2-dichloro ethylimine through an addition reaction, then obtains 1-hydroxy-4-p-tolylimidazole-2-methyl aldoxime through a cyclization reaction under alkaline conditions, and then obtains the target product through chlorination and oxidation. Compared with the existing synthesis method, the application innovatively constructs the imidazole ring, generates a relatively stable intermediate containing aldoxime structure, and then generates a cyano group mildly and greenly. The design not only simplifies the reaction path, but also significantly reduces the safety risk in industrial production.

Description

Technical Field

[0001] This invention relates to a 4-chloro-2-cyano-5-p-tolyl-1 H The chemical synthesis method of -imidazole belongs to the field of pharmaceutical intermediate synthesis. Background Technology

[0002] 4-Chloro-2-cyano-5-p-Tolyl-1 H -Imidazole (CAS: 120118-14-1), molecular formula: C 11 H8ClN3, with a relative molecular mass of 217.66, has the following chemical structure: It is a synthetic, highly effective fungicide, cyazofamid (4-chloro-2-cyano- N , N The key intermediate of 4-chloro-2-cyano-5-p-tolyl-1-sulfonamide. Cyazofamid is a highly effective fungicide widely used in agricultural production, exhibiting good control effects against various plant diseases such as downy mildew, downy mildew, and late blight. Its advantages lie in its high control activity, low toxicity, and long-lasting effect, thus it has been widely used in domestic and international markets, demonstrating significant development potential. In the synthetic route of cyazofamid, 4-chloro-2-cyano-5-p-tolyl-1-sulfonamide is involved. H -Imidazole is one of the key intermediates. The main difficulties in synthesizing this intermediate lie in the construction of the imidazole ring and the accurate introduction and stable control of the cyano functional group.

[0003] There is currently 4-chloro-2-cyano-5-p-tolyl-1 H There are two methods for synthesizing imidazole: A. Using p-methylacetophenone as a raw material, 2-carbonyl-2-(p-tolyl)acetaldehyde is first prepared by reaction in the presence of an oxidizing agent (such as SeO2). Then, it undergoes a cyclization reaction with ammonium salts and glyoxal to construct an imidazole ring. Following oxidation, cyanation, and chlorination, 4-chloro-2-cyano-5-p-tolyl-1-carbonyl is obtained. H -Imidazole. This type of synthesis involves complex routes and lengthy steps, limiting its efficiency for industrial production.

[0004] B. Starting with p-methylacetophenone, it is first reacted with liquid bromine to produce 2,2-dibromo-4'-methylacetophenone, then reacted with glyoxal and hydroxylamine to prepare 1-hydroxy-4-p-tolyl-2-methylimidazole-3-oxide, which is then subjected to chlorination to obtain 4-chloro-2-cyano-5-p-tolyl-1-methylacetophenone. H -Imidazole. This route is relatively simple, but the resulting nitrogen oxide intermediates have low yields and poor stability, posing a high risk in industrial production. Summary of the Invention

[0005] For existing methods of synthesizing 4-chloro-2-cyano-5-p-tolyl-1 H The imidazole process route suffers from problems such as lengthy steps, low industrial efficiency, poor intermediate stability, low yield, and high production risk. This invention successfully develops a new route that is simple to operate, has stable intermediates, and a high yield.

[0006] The present invention describes a 4-chloro-2-cyano-5-p-tolyl-1 H The synthesis method of -imidazole is represented by the following chemical reaction formula:

[0007] Includes the following steps: Step 1: In the presence of a Lewis acid, dichloroacetonitrile reacts with toluene in an organic solvent to give intermediate I (1-p-tolyl-2,2-dichloroethyleneimine). Step 2: In the presence of a base, intermediate I reacts with dioxime in an organic solvent to give intermediate II (1-hydroxy-4-p-tolylimidazol-2-formaldehyde oxime). Step 3: Intermediate II is first chlorinated with a chlorinating agent, and then oxidized to give 4-chloro-2-cyano-5-p-tolyl-1- H -Imidazole.

[0008] Furthermore, in the above technical solution, the Lewis acid mentioned in the first step is aluminum trichloride.

[0009] Furthermore, in the above technical solution, after the first step reaction is completed, 10% dilute hydrochloric acid that has been fully cooled is added to quench the reaction, followed by extraction with ice-cold diethyl ether, and the crude product is recrystallized with ice-cold ethanol.

[0010] Furthermore, in the above technical solution, the base mentioned in the second step is selected from triethylamine, DBU, DBN or DMAP, and the reaction is carried out under reflux conditions.

[0011] Furthermore, in the above technical solution, the organic solvent in the second step is selected from ethanol, acetonitrile, ethyl acetate, or dichloromethane.

[0012] Furthermore, in the above technical solution, the molar ratio of intermediate I to oxime in the second step is 1:1-2.

[0013] Furthermore, in the above technical solution, the third step is as follows: intermediate II is reacted with a chlorinated reagent in acetonitrile at room temperature, then extracted and concentrated, an oxidant is added to the concentrate, and the reaction is then heated.

[0014] Furthermore, in the above technical solution, the chlorination reagent in the third step is... N -Chlorosuccinimide.

[0015] Furthermore, in the above technical solution, the oxidation reaction described in the third step is Swern oxidation.

[0016] Compared to existing technologies with their long reaction steps and the high risks and pollution associated with cyanation reactions, this invention innovatively constructs an imidazole ring through a cyclization reaction with dioxime, generating a relatively stable intermediate containing an aldehyde oxime structure, thus achieving a mild and environmentally friendly cyano group formation. This design not only simplifies the reaction pathway but also significantly reduces safety risks in industrial production. Detailed Implementation

[0017] The present invention will be further described in detail below with reference to specific embodiments. Example 1

[0018] Under nitrogen protection, 50 mL of anhydrous dichloromethane and 29.3 g of anhydrous aluminum trichloride were added to a dry three-necked flask, and the reaction system was cooled to 0–5 °C in an ice-water bath. 22.0 g of dichloroacetonitrile was dissolved in 10 mL of anhydrous dichloromethane and transferred to a constant-pressure dropping funnel. This solution was slowly added dropwise to the suspension under vigorous stirring, with the internal temperature controlled to not exceed 5 °C during the addition. After the addition was complete, stirring was continued for 30 min at the same temperature to ensure complete complexation. Then, 25 mL of toluene was dissolved in 10 mL of anhydrous dichloromethane and slowly added dropwise to the reaction system under cooling conditions, with the addition temperature controlled to not exceed 10 °C. After the addition was complete, the reaction system was slowly heated to reflux and reacted for 4 h, with TLC monitoring the reaction progress. After the reaction was complete, the mixture was cooled to 0–5 °C in an ice bath, and 10% ice-cold dilute hydrochloric acid was slowly added dropwise until the pH reached 3. The mixture was transferred to a separatory funnel and separated. The aqueous phase was extracted with ice-cold diethyl ether. The organic phases were combined, washed with saturated brine, dried, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from ice-cold ethanol and dried to give 36.1 g of intermediate I (1-p-tolyl-2,2-dichloroethyleneimine), with a yield of 89.3% and a purity of 96.1%.

[0019] 32.3 g of intermediate I and 14.1 g of dioxime were added sequentially to a dry round-bottom flask, followed by 60 mL of anhydrous ethanol. The mixture was then stirred magnetically until completely dissolved. 32.4 g of triethylamine was added to the reaction mixture as an acid-binding agent, and the mixture was stirred until homogeneous. The reaction system was heated to reflux and stirred for 3 h, with the reaction progress monitored by TLC. After the reaction was complete, the system was cooled in an ice-water bath for 2 h to allow crystallization. The solid was collected by filtration, and the filter cake was washed with a small amount of cold ethanol and dried to obtain the crude product. The crude product was recrystallized from ice-cold ethanol and dried to obtain 25.2 g of intermediate II (1-hydroxy-4-p-toluylimidazole-2-carboxaldehyde oxime), with a yield of 72.5% and a purity of 96.7%.

[0020] Add 21.7 g of intermediate II and 100 mL of anhydrous acetonitrile to a dry round-bottom flask, and stir until completely dissolved. Slowly add 14.7 g in portions. N -Chlorosuccinimide (NCS) was reacted with stirring at room temperature for 4 h, and the reaction progress was monitored by TLC. The reaction mixture was then extracted with ethyl acetate and water, and the organic phase was collected and concentrated. 100 mL of anhydrous dichloromethane and 30.4 g of anhydrous triethylamine were added to the concentrate, and the mixture was cooled to -10°C in an ice-water bath. In another flask, 15.2 g of oxalyl chloride was dissolved in 20 mL of anhydrous dichloromethane, cooled to the same temperature, and then 14.2 mL of DMSO was added and stirred for a few minutes to activate the reaction. The activated DMSO / oxalyl chloride solution was slowly added dropwise to the reaction flask containing the substrate. After the addition was complete, the ice bath was removed, and the mixture was slowly heated to room temperature with stirring for 1 h. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by recrystallization from ethyl acetate to obtain the final product 4-chloro-2-cyano-5-p-tolyl-1- H -Imidazole 16.7 g, yield 76.7%, purity 98.3%. Example 2

[0021] Under nitrogen protection, 50 mL of anhydrous dichloromethane and 32.0 g of anhydrous aluminum trichloride were added to a dry three-necked flask, and the reaction system was cooled to 0–5 °C in an ice-water bath. 22.0 g of dichloroacetonitrile was dissolved in 10 mL of anhydrous dichloromethane and transferred to a constant-pressure dropping funnel. This solution was slowly added dropwise to the suspension under vigorous stirring, with the internal temperature controlled to not exceed 5 °C during the addition. After the addition was complete, the mixture was stirred for 30 min at the same temperature to ensure complete complexation. Then, 25 mL of toluene was dissolved in 10 mL of anhydrous dichloromethane and slowly added dropwise to the reaction system under cooling conditions, with the addition temperature controlled to not exceed 10 °C. After the addition was complete, the reaction system was slowly heated to reflux and reacted for 4 h, with TLC monitoring the reaction progress. After the reaction was complete, the mixture was cooled to 0–5 °C in an ice bath, and 10% ice-cold dilute hydrochloric acid was slowly added dropwise until the pH reached 3. The mixture was transferred to a separatory funnel and separated. The aqueous phase was extracted with ice-cold diethyl ether. The organic phases were combined, washed with saturated brine, dried, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from ice-cold ethanol and dried to give 35.0 g of intermediate I (1-p-tolyl-2,2-dichloroethyleneimine), with a yield of 86.6% and a purity of 97.4%.

[0022] 32.3 g of intermediate I and 16.9 g of dioxime were added sequentially to a dry round-bottom flask, followed by 60 mL of anhydrous ethanol. The mixture was then stirred magnetically until completely dissolved. 24.3 g of triethylamine was added to the reaction mixture as an acid-binding agent, and the mixture was stirred until homogeneous. The reaction system was heated to reflux and stirred for 4 h, with the reaction progress monitored by TLC. After the reaction was complete, the system was cooled in an ice-water bath for 2 h to allow crystallization. The solid was collected by filtration, and the filter cake was washed with a small amount of cold ethanol and dried to obtain the crude product. The crude product was recrystallized from ice-cold ethanol and dried to obtain 23.8 g of intermediate II (1-hydroxy-4-p-toluylimidazole-2-carboxaldehyde oxime), with a yield of 68.5% and a purity of 97.2%.

[0023] Add 21.7 g of intermediate II and 100 mL of anhydrous acetonitrile to a dry round-bottom flask, and stir until completely dissolved. Slowly add 16.0 g in portions. N -Chlorosuccinimide (NCS) was reacted with stirring at room temperature for 4 h, and the reaction progress was monitored by TLC. The reaction mixture was then extracted with ethyl acetate and water, and the organic phase was collected and concentrated. 100 mL of anhydrous dichloromethane and 30.4 g of anhydrous triethylamine were added to the concentrate, and the mixture was cooled to -10°C in an ice-water bath. In another flask, 19.0 g of oxalyl chloride was dissolved in 20 mL of anhydrous dichloromethane, cooled to the same temperature, and then 14.2 mL of DMSO was added and stirred for a few minutes to activate the reaction. The activated DMSO / oxalyl chloride solution was slowly added dropwise to the reaction flask containing the substrate. After the addition was complete, the ice bath was removed, and the mixture was slowly heated to room temperature with stirring for 1 h. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by recrystallization from ethyl acetate to obtain the final product 4-chloro-2-cyano-5-p-tolyl-1- H -Imidazole 17.0 g, yield 78.1%, purity 99.2%. Example 3

[0024] Under nitrogen protection, 50 mL of anhydrous dichloromethane and 40.0 g of anhydrous aluminum trichloride were added to a dry three-necked flask, and the reaction system was cooled to 0–5 °C in an ice-water bath. 22.0 g of dichloroacetonitrile was dissolved in 10 mL of anhydrous dichloromethane and transferred to a constant-pressure dropping funnel. This solution was slowly added dropwise to the suspension under vigorous stirring, with the internal temperature controlled to not exceed 5 °C during the addition. After the addition was complete, the mixture was stirred for 30 min at the same temperature to ensure complete complexation. Then, 26 mL of toluene was dissolved in 10 mL of anhydrous dichloromethane and slowly added dropwise to the reaction system under cooling conditions, with the addition temperature controlled to not exceed 10 °C. After the addition was complete, the reaction system was slowly heated to reflux and reacted for 4 h, with TLC monitoring the reaction progress. After the reaction was complete, the mixture was cooled to 0–5 °C in an ice bath, and 10% ice-cold dilute hydrochloric acid was slowly added dropwise until the pH reached 3. The mixture was transferred to a separatory funnel and separated. The aqueous phase was extracted with ice-cold diethyl ether. The organic phases were combined, washed with saturated brine, dried, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was recrystallized from ice-cold ethanol and dried to give 36.5 g of intermediate I (1-p-tolyl-2,2-dichloroethyleneimine), with a yield of 90.3% and a purity of 98.2%.

[0025] 32.3 g of intermediate I and 21.1 g of dioxime were sequentially added to a dry round-bottom flask, followed by 60 mL of anhydrous ethanol. The mixture was then stirred magnetically until completely dissolved. 24.4 g of DBU was added to the reaction mixture as an acid-binding agent, and the mixture was stirred until homogeneous. The reaction system was heated to reflux and stirred for 1 h, with the reaction progress monitored by TLC. After the reaction was complete, the system was cooled in an ice-water bath for 2 h to allow crystallization. The solid was collected by filtration, and the filter cake was washed with a small amount of cold ethanol and dried to obtain the crude product. The crude product was recrystallized from ice-cold ethanol and dried to obtain 30.8 g of intermediate II (1-hydroxy-4-p-toluylimidazole-2-carboxaldehyde oxime), with a yield of 88.6% and a purity of 97.7%.

[0026] Add 21.7 g of intermediate II and 100 mL of anhydrous acetonitrile to a dry round-bottom flask, and stir until completely dissolved. Slowly add 16.0 g in portions. N-Chlorosuccinimide (NCS) was reacted with stirring at room temperature for 3 h, and the reaction progress was monitored by TLC. The reaction mixture was then extracted with ethyl acetate and water, and the organic phase was collected and concentrated. 100 mL of anhydrous dichloromethane and 30.4 g of anhydrous triethylamine were added to the concentrate, and the mixture was cooled to -10°C in an ice-water bath. In another flask, 19.0 g of oxalyl chloride was dissolved in 20 mL of anhydrous dichloromethane, cooled to the same temperature, and then 14.2 mL of DMSO was added and stirred for a few minutes to activate the reaction. The activated DMSO / oxalyl chloride solution was slowly added dropwise to the reaction flask containing the substrate. After the addition was complete, the ice bath was removed, and the mixture was slowly heated to room temperature with stirring for 1 h. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by recrystallization from ethyl acetate to obtain the final product 4-chloro-2-cyano-5-p-tolyl-1- H -Imidazole 16.4 g, yield 75.3%, purity 98.5%.

[0027] The above embodiments describe the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from its principles, and all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A 4-chloro-2-cyano-5-p-tolyl-1 H The method for synthesizing α-imidazole is characterized by, Includes the following steps: Step 1: In the presence of a Lewis acid, dichloroacetonitrile reacts with toluene in an organic solvent to give 1-p-tolyl-2,2-dichloroethyleneimine; Step 2: In the presence of a base, 1-p-tolyl-2,2-dichloroethyleneimine reacts with ethylenedioxime in an organic solvent to give 1-hydroxy-4-p-tolylimidazol-2-carboxaldehyde oxime; Step 3: 1-Hydroxy-4-p-Tolylimidazol-2-carboxaldehyde oxime is first chlorinated with a chlorinating agent, and then oxidized to give 4-chloro-2-cyano-5-p-tolyl-1-carboxaldehyde oxime. H -Imidazole.

2. The 4-chloro-2-cyano-5-p-tolyl-1 ... H The method for synthesizing -imidazole is characterized by: In the first step, the Lewis acid is aluminum trichloride.

3. The 4-chloro-2-cyano-5-p-tolyl-1 ... H The method for synthesizing -imidazole is characterized by: In the first step, after the reaction is complete, the mixture is quenched with fully cooled 10% dilute hydrochloric acid, extracted with ice-cold diethyl ether, and the crude product is recrystallized with ice-cold ethanol.

4. The 4-chloro-2-cyano-5-p-tolyl-1 ... H The method for synthesizing -imidazole is characterized by: In the second step, the base is selected from triethylamine, anhydrous potassium carbonate, or ammonium carbonate, and the reaction is carried out under reflux conditions.

5. The 4-chloro-2-cyano-5-p-tolyl-1 ... H The method for synthesizing -imidazole is characterized by: In the second step, the organic solvent is selected from ethanol, acetonitrile, ethyl acetate or dichloromethane.

6. The 4-chloro-2-cyano-5-p-tolyl-1 ... H The method for synthesizing -imidazole is characterized by: In the second step, the molar ratio of 1-p-tolyl-2,2-dichloroethyleneimine to ethylenedioxime is 1:1-2.

7. The 4-chloro-2-cyano-5-p-tolyl-1 ... H The method for synthesizing -imidazole is characterized by: The third step involves reacting 1-hydroxy-4-p-toluylimidazol-2-carboxaldehyde oxime with a chlorinated reagent in acetonitrile at room temperature, followed by extraction and concentration. An oxidizing agent is then added to the concentrate, and the mixture is heated to react further.

8. The 4-chloro-2-cyano-5-p-tolyl-1 ... H The method for synthesizing -imidazole is characterized by: In the third step, the chlorination reagent is N -Chlorosuccinimide.

9. The 4-chloro-2-cyano-5-p-tolyl-1 ... H The method for synthesizing -imidazole is characterized by: In the third step, the oxidation reaction is performed using Swern oxidation.

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