1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole and synthetic method thereof

Abstract

The invention discloses 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole and a synthesis method of the 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole, and belongs to the technical field of organic synthesis, and the 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole has the following structural formula shown in the description. The invention also discloses a chemical synthesis method of the compound, the compound 2, 4-dichloro-5-aminotrifluorotoluene is used as a starting raw material, a target product is obtained through acylation, nitration, ammonolysis, dehydration cyclization and condensation five-step reaction, and the total conversion rate of the prepared target product reaches more than 60%.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and more specifically, to a 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole and its synthesis method. Background Technology

[0002] Aminofluridine (also known as aminofluridine) is a dinitroaniline herbicide. Its synthesis method is described in US Patent No. 3764623 (filed September 3, 1970), US Patent No. 05448322A (filed March 5, 1974), and Chinese Patent No. CN200910153813.3 (filed November 16, 2009). Aminofluridine has excellent contact and pre-emergence weed control properties and is widely used in cereals and non-cultivated land to control annual and perennial grass weeds. Our research found that the metabolic process of this drug in vivo first generates a nitrosamine intermediate, which is then converted into the compound shown in formula (VI) as the final metabolite. The metabolic process is shown in the figure below. Starting with aminofluridine, it undergoes partial reduction to generate a nitrosamine compound, which is then dehydrated and cyclized to synthesize the compound shown in formula (VI).

[0003]

[0004] The compound shown in formula (VI) may serve as a potential stress-resistant active molecule for controlling annual and perennial grass weeds in cereals and non-cultivated lands. Establishing a chemical synthesis method for this compound is of great significance for further exploring its mechanism of action in plants. However, a method for synthesizing the compound shown in formula (VI) has not yet been discovered.

[0005] Therefore, there is an urgent need to provide an economical and efficient synthetic route for the compound as shown in formula (VI). Summary of the Invention

[0006] To address the problems existing in the prior art, the first objective of this invention is to provide a method for synthesizing 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole. This method uses 2,4-dichloro-5-aminotrifluorotoluene as a starting material and proceeds through five steps: acylation, nitration, ammonolysis, dehydration and cyclization, and condensation, to obtain the target product, with a total conversion rate exceeding 60%. The second objective of this invention is to provide 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole, a compound that can be used to further explore its mechanism of action in plants.

[0007] To solve the above problems, the present invention adopts the following technical solution.

[0008] A method for synthesizing 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole, the chemical equation for which is shown below:

[0009]

[0010] The preparation steps are as follows:

[0011] S1: Acylation reaction: 2,4-dichloro-5-aminotrifluorotoluene as shown in formula (I) is reacted with a carboxyl activating agent in the presence of an organic base to give N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide as shown in formula (II);

[0012] S2: Nitration reaction: The N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide obtained in step S1 reacts with a nitrating agent under the action of concentrated sulfuric acid or fuming sulfuric acid to obtain N-(2,4-dichloro-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in formula (III);

[0013] S3: Ammonolysis reaction: N-(2,4-dichloro-3-nitro-5-trifluoromethylphenyl)-propionamide obtained in step S2 reacts with ammonia under a certain pressure to obtain N-(2,4-diamino-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in formula (IV);

[0014] S4: Dehydration cyclization reaction: The N-(2,4-diamino-3-nitro-5-trifluoromethylphenyl)-propionamide obtained in step S3 is cyclized under the action of an acid catalyst to give 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole as shown in formula (V);

[0015] S5: Alkylation reaction: The 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole obtained in step S4 reacts with an alkylating agent under alkaline catalysis to give the target product as shown in formula (VI).

[0016] Further, in step S1, the carboxyl activating agent is an acyl halide, an active ester, an active carbodiimide, or an active acyl imidazole; the amount of the carboxyl activating agent used is 1.0-2.0 times the molar amount of 2,4-dichloro-5-aminotrifluorotoluene shown in formula (I); preferably 1.05-1.2 times. The acyl halide is propionyl chloride or propionyl bromide; the active ester is N-hydroxysuccinimide ester, p-nitrophenyl ester, or pentafluorophenyl ester; the active carbodiimide is N,N-dicyclohexylcarbodiimide or N,N-diisopropylcarbodiimide; the active acyl imidazole is 1-acetylimidazole, N,N'-carbonyldiimidazole, or N-heptafluorobutyrylimidazole; the carboxyl activating agent is preferably propionyl chloride. Reactive esters, reactive carbon diimides, or reactive acyl imidazoles also show good reaction results. However, due to their higher cost and the fact that they leave residue fragments after the reaction, they are generally used in the synthesis of high-value drugs where the reaction conditions are more demanding.

[0017] Furthermore, in step S1, the organic base is trimethylamine, triethylamine, diisopropylethylamine, tributylamine, pyridine, or N,N-dimethylaminopyridine; the amount of organic base used is 1.0-4.0 times the molar amount of 2,4-dichloro-5-aminotrifluorotoluene shown in formula (I); preferably 1.1-1.5 times.

[0018] Further, in step S2, the concentrated sulfuric acid has a mass concentration of 98%; the fuming sulfuric acid has a mass concentration of 0-20%, and the amounts of both concentrated sulfuric acid and fuming sulfuric acid are 2.0-20.0 times the molar amount of N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide as shown in formula (II); preferably 3.0-5.0 times; the nitrating agent is concentrated nitric acid with a mass concentration of 63-97%; the amount of the nitrating agent (pure) is 2.0-3.0 times the molar amount of N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide as shown in formula (II). If 63% concentrated nitric acid is used, the nitric acid can be added to the concentrated sulfuric acid all at once, and then N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide as shown in formula (II) can be added in batches. After the addition is complete, the reaction is maintained at 60-110°C for 4-10 hours. However, using concentrated nitric acid with a mass concentration of 97% poses certain risks. It is advisable to first mix the compound with concentrated sulfuric acid, and then slowly add the nitric acid dropwise. After the addition is complete, maintain the temperature at 30-60℃ for 2-5 hours to ensure complete reaction. It should be noted that batch nitration reactions always carry certain safety hazards; therefore, the use of a microchannel continuous flow reactor is highly recommended for this reaction.

[0019] Furthermore, in step S3, the ammonia is one or a mixture of two types of ammonia solution or liquid ammonia with a mass concentration of 10-30%. The amount of ammonia used is 4.0-20.0 times, preferably 6.0-10.0 times, the molar amount of N-(2,4-dichloro-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in formula (III); the reaction pressure is 0.1-2.0 MPa, preferably 0.1-1.0 MPa; the reaction temperature is 30-120℃, preferably 100-120℃; and the reaction time is 4-30 h. The amount of ammonia used, the reaction temperature, and the pressure all significantly affect the reaction time.

[0020] Furthermore, in step S4, the acid catalyst is an organic acid or an inorganic acid; the organic acid is acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, or methanesulfonic acid; the inorganic acid is sulfuric acid, phosphoric acid, or polyphosphoric acid; the amount of acid catalyst used is 2.0-50.0 times the molar amount of N-(2,4-diamino-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in formula (IV); preferably 2.0-5.0 times.

[0021] Further, in step S5, the alkylating agent is chloropropane, bromopropane, iodopropane, dipropyl sulfate, or dipropyl carbonate; bromopropane is preferred considering cost and safety. The amount of alkylating agent used is 1.0-2.0 times, preferably 1.1-1.3 times, the molar amount of 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole as shown in (V); the base is an inorganic base, an organic base, or a metal hydride; the inorganic base is sodium carbonate, potassium carbonate, calcium carbonate, calcium oxide, lithium hydroxide, sodium hydroxide, or potassium hydroxide; the organic base is an amine compound or a metal salt of an alcohol, and the amine compound... The compound is trimethylamine, triethylamine, diisopropylethylamine, tributylamine, pyridine, piperidine, or N,N-dimethylaminopyridine; the metal salt of the alcohol is sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide; the metal hydride is lithium hydride, sodium hydride, potassium hydride, or calcium hydride; the amount of the base catalyst is 1.0-4.0 times the molar amount of 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole as shown in (V). The optimal amount varies depending on the base used. If solid powdered potassium carbonate is used, 3.0-4.0 times the amount is preferable; if potassium tert-butoxide, which is more basic, is used, 1.0-1.3 times the amount is preferable.

[0022] Furthermore, the acylation reaction in step S1 is carried out in a solvent at a temperature of -20 to 80°C, preferably 20 to 40°C; it can be carried out at room temperature; the reaction time is 2 to 10 hours; the solvent is one or more of dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, toluene, xylene, tetrahydrofuran, 1,4-dichlorohexacyclohexane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; the present invention does not impose specific restrictions on the amount of solvent and alkali used, but considering cost and efficiency, the solvent and amount used can be sufficient to dissolve the substrate completely;

[0023] The dehydration cyclization reaction in step S4 is carried out in a solvent at a temperature of 80-180°C, particularly preferably at the reflux temperature of the solvent, for a reaction time of 3-9 hours. The solvent is an organic acid, an inert aromatic solvent, or a polar aprotic solvent. The organic acid is acetic acid, propionic acid, or trifluoroacetic acid; the inert aromatic solvent is toluene, xylene, chlorobenzene, or dichlorobenzene; the polar aprotic solvent is N,N-dimethylformamide, N,N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamine, ethylene glycol dimethyl ether, or diethylene glycol dimethyl ether.

[0024] The alkylation reaction in step S5 is carried out in a solvent at a temperature of -20 to 180°C, preferably 20 to 80°C, and particularly preferably at the reflux temperature of the solvent; the reaction time is 3 to 8 hours; the solvent is dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, toluene, xylene, tetrahydrofuran, 1,4-dichlorohexacyclohexane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone.

[0025] Furthermore, step S3 can be carried out with or without the presence of a phase transfer catalyst, surfactant, or dispersant.

[0026] The present invention also provides a 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole, which is synthesized by the above-mentioned method for synthesizing 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole.

[0027] Compared with the prior art, the advantages of this invention are:

[0028] I. This scheme can synthesize 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole, a metabolite obtained by the action of ambroxol in plants, through chemical methods. This is of great significance for studying the mechanism of action of this metabolite in plants.

[0029] II. The average yield of each step in the chemical method provided in this scheme for synthesizing the metabolite 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole obtained after the action of ambroxol in plants is over 80%, and the total yield is over 60%. Attached Figure Description

[0030] Figure 1 The electrospray ionization mass spectrum (ESI-MS) of 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole in Example 1 is shown.

[0031] Figure 2 The electrospray ionization mass spectrum of 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole in Example 1 is shown in the mass spectrum. 1 (H-NMR spectrum). Detailed Implementation

[0032] The specific preparation process of this invention is as follows:

[0033] Example 1:

[0034] The preparation process of the compound shown in Formula VI is as follows:

[0035]

[0036] The preparation steps are as follows:

[0037] (a) Preparation of N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide as shown in Formula II:

[0038] In a 250 mL three-necked flask, add 35.0 g of propionic acid and 56.0 g of thionyl chloride. Start stirring and heat to 45-50 °C for 2 hours. Then, reflux at approximately 80 °C for 5 minutes, and begin distilling off the fraction, collecting it as propionyl chloride for later use. Add 93.0 g (0.403 mol) of 2,4-dichloro-5-aminotrifluorotoluene (as shown in Formula I), 280 mL of dichloroethane, and 47.9 g (0.474 mol) of triethylamine sequentially to a 500 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. Stir until dissolved, and add the prepared propionyl chloride dropwise at 20-30 °C. After the addition is complete, continue stirring for 2 hours. After the reaction is complete, add the reaction solution to 200 mL of water, stir, allow to stand, and allow to separate into layers. Wash twice with 200 mL of water each time. The organic phase was concentrated to dryness to obtain crude N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide as shown in Formula II, 115.0 g, with a yield of 99.5%. The crude N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide as shown in Formula II does not require purification and can be used for later use.

[0039] (II) Preparation of N-(2,4-dichloro-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in Formula III:

[0040] 115.0 g (0.402 mol) of crude N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide prepared in step (I) and 200 g (2.0 mol) of 98% concentrated sulfuric acid were added to a 500 mL four-necked flask equipped with a mechanical stirrer, thermometer, and explosion vent. Stirring was started, and 78 g (1.2 mol) of 97% nitric acid was added dropwise while controlling the temperature at 20-40℃. After the addition was complete, the reaction was carried out at 40-50℃ for 3 h. After the reaction was complete, the reaction solution was slowly poured into 600 g of ice water, precipitating a solid. The solid was filtered, washed with water, and yielded wet N-(2,4-dichloro-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in Formula III, yielding 121.0 g dry, with a yield of 91.4%.

[0041] (III) Preparation of N-(2,4-diamino-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in Formula IV:

[0042] Wet N-(2,4-dichloro-3-nitro-5-trifluoromethylphenyl)-propionamide (121.0 g dry weight, 0.365 mol) obtained in step (II) was added to a 1L autoclave along with 200 g of 20% ammonia solution. The autoclave was then covered, and ammonia gas was introduced to a pressure of 0.1 MPa. The temperature was raised to 110°C and maintained for 8 hours. The temperature was then lowered to room temperature, filtered, washed with water until neutral, and dried to obtain 96.8 g of dry N-(2,4-diamino-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in formula (IV), with a yield of 90.7%.

[0043] (iv) Preparation of 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole as shown in Formula V:

[0044] 96.8 g (0.330 mol) of dried N-(2,4-diamino-3-nitro-5-trifluoromethylphenyl)-propionamide obtained in step (III) was added to 99 g (1.6 mol) of acetic acid, heated to 120 °C, refluxed for 4 h, then cooled to about 60 °C, concentrated to dryness under reduced pressure, and the residue was diluted with 500 mL of water. The pH was adjusted to 8.5-9.0 with ammonia water, stirred for 1 h, and a brown solid precipitated. The solid was filtered, dried, and 84.1 g of 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole as shown in Formula V was obtained, with a yield of 92.4%.

[0045] (v) Preparation of 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole as shown in Formula VI:

[0046] Add 84.1 g (0.307 mol) of 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole obtained in step (IV), 127.4 g (0.921 mol) of powdered potassium carbonate, and 300 mL of DMF to a 500 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. Heat to 65-70 °C and begin adding 49.1 g (0.399 mol) of bromopropane dropwise. After the addition is complete, continue the reaction at this temperature for 4 hours. Cool to room temperature, filter, and concentrate the filtrate under reduced pressure to remove about half of the solvent. Add 300 mL of water and 500 mL of toluene, stir for 30 min, and allow the layers to separate. Wash the aqueous phase with 200 mL of water twice. Dry the resulting organic phase with anhydrous sodium sulfate, add a small amount of silica gel for adsorption, filter, and concentrate the filtrate to obtain 88.7 g of a yellow oily substance, which is the target compound with a purity of 98.5% and a yield of 91.4%; the overall yield is 69.4%.

[0047] Example 2:

[0048] (a) Preparation of N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide as shown in Formula II:

[0049] 93 g (0.403 mol) of 2,4-dichloro-5-aminotrifluorotoluene (as shown in Formula I), 280 mL of dichloroethane, 48.0 g (0.475 mol) of triethylamine, and 72.0 g (0.444 mol) of N,N'-carbonyldiimidazole were sequentially added to a 500 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. The mixture was stirred until dissolved, and 31 g (0.419 mol) of propionic acid was added dropwise at 20-30 °C. After the addition was complete, stirring was continued for 3 hours. After the reaction was complete, the reaction solution was added to 200 mL of water, stirred, allowed to stand, and allowed to separate into layers. The layers were then washed twice with 200 mL of water each. The organic phase was concentrated to dryness to obtain 114.5 g of crude N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide (as shown in Formula II), with a yield of 99.0%. The crude N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide as shown in Formula II does not require purification and can be used as is.

[0050] (II) Preparation of N-(2,4-dichloro-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in Formula III:

[0051] 260g of 98% (2.6mol) concentrated sulfuric acid and 170g of 63% (1.7mol) nitric acid were added to a 500mL four-necked flask equipped with a mechanical stirrer, thermometer, and explosion vent. After mixing thoroughly, 114.5g (0.400mol) of crude N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide prepared in step (I) was added in batches. After the addition was complete, the mixture was reacted at 40-50℃ for 6 hours. After the reaction was completed, the reaction solution was slowly poured into 800g of ice water, and a solid precipitated. The solid was filtered, washed with water, and the wet product of N-(2,4-dichloro-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in Formula III was obtained, yielding 106.5g dry, with a yield of 80.4%.

[0052] (III) Preparation of N-(2,4-diamino-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in Formula IV:

[0053] Wet N-(2,4-dichloro-3-nitro-5-trifluoromethylphenyl)-propionamide (106.5 g dry weight, 0.322 mol), 100 g water, and 1.0 g sodium cetylbenzenesulfonate were added to a 1 L autoclave. The autoclave was then covered, and 70 g ammonia gas was introduced. The temperature was raised to 105 °C and maintained for 3 h. The temperature was then lowered to room temperature, filtered, washed with water until neutral, and dried to obtain 90.6 g of dry N-(2,4-diamino-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in formula (IV), with a yield of 96.4%.

[0054] (iv) Preparation of 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole as shown in Formula V:

[0055] 90.6 g (0.310 mol) of dried N-(2,4-diamino-3-nitro-5-trifluoromethylphenyl)-propionamide obtained in step (III) was added to 114 g (1.54 mol) of propionic acid and 30 g of polyphosphoric acid. The mixture was heated to 140 °C and refluxed for 3 h. Then, it was cooled to about 80 °C and the propionic acid was concentrated to dryness under reduced pressure. 600 mL of ice water was added to the residue, and the pH was adjusted to 8.0-9.0 with ammonia water while stirring. The brown solid was filtered, washed with water until neutral, and dried to obtain 77.1 g of 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole as shown in Formula V, with a yield of 90.6%.

[0056] (v) Preparation of 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole as shown in Formula VI:

[0057] 77.1 g (0.281 mol) of 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole obtained in step (IV), 33.1 g (0.295 mol) of potassium tert-butoxide, and 280 mL of THF were added to a 500 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. The temperature was raised to 40-45 °C, and 36.3 g (0.295 mol) of bromopropane was added dropwise. After the addition was complete, the reaction was maintained at this temperature for 3 h. The mixture was concentrated to dryness under reduced pressure, and 300 mL of water and 500 mL of toluene were added. Subsequent processing was the same as in Example 1, yielding 82.8 g of the target compound, with a yield of 92.5%; the overall yield was 64.3%.

[0058] Example 3:

[0059] (a) Preparation of N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide as shown in Formula II:

[0060] 93 g (0.403 mol) of 2,4-dichloro-5-aminotrifluorotoluene (as shown in Formula I), 280 mL of dichloroethane, 47.9 g (0.474 mol) of triethylamine, and 86.7 g (0.420 mol) of N,N-dicyclohexylcarbodiimide were sequentially added to a 500 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. The mixture was stirred until dissolved, and 31 g (0.419 mol) of propionic acid was added dropwise at 20-30 °C. After the addition was complete, stirring was continued for 2 hours. After the reaction was complete, the reaction solution was added to 200 mL of water, stirred, allowed to stand, and allowed to separate into layers. The layers were then washed twice with 200 mL of water each. The organic phase was concentrated to dryness to obtain 114.0 g of crude N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide (as shown in Formula II), with a yield of 98.6%. The crude N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide as shown in Formula II does not require purification and can be used as is.

[0061] (II) Preparation of N-(2,4-dichloro-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in Formula III:

[0062] 114.0 g (0.398 mol) of crude N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide obtained in step (I) was mixed with 210 g of fuming sulfuric acid (105%) and 160 g of nitric acid (63%) (1.6 mol), and then fed into a microchannel continuous flow reactor. The mixture was held at 80-90°C for 15 seconds. The material at the outlet was placed in 600 g of crushed ice to precipitate a solid. The solid was filtered, washed with water, and a wet product of N-(2,4-dichloro-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in Formula III was obtained, yielding 110.0 g dry, with a yield of 83.4%.

[0063] (III) Preparation of N-(2,4-diamino-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in Formula IV:

[0064] Add the wet product (110 g dry weight, 0.332 mol) of N-(2,4-dichloro-3-nitro-5-trifluoromethylphenyl)-propionamide obtained in step (II), 100 g of 28% ammonia water, and 1.0 g of sodium hexadecylbenzenesulfonate to a 1 L autoclave. Cover the autoclave and then purge with ammonia gas to a pressure of 0.02 MPa. Heat to 110 °C and maintain for 4 h. Cool to room temperature, filter, wash with water until neutral, and dry to obtain 91.2 g of dry N-(2,4-diamino-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in formula (IV), with a yield of 93.9%.

[0065] (iv) Preparation of 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole as shown in Formula V:

[0066] 91.2 g (0.312 mol) of dried N-(2,4-diamino-3-nitro-5-trifluoromethylphenyl)-propionamide obtained in step (III), 90 g of acetic acid, and 10 g (0.1 mol) of 98% sulfuric acid were heated to 120 °C and refluxed for 3 h. The mixture was then cooled to about 60 °C, concentrated under reduced pressure, and about 60% of the acetic acid was recovered. 500 mL of water was added for dilution, and 30% liquid alkali was added dropwise to adjust the pH to 8.0-8.5 while stirring. The mixture was stirred for 1 h, and a brown solid precipitated. The solid was filtered, dried, and 78.0 g of 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole as shown in Formula V was obtained, with a yield of 91.1%.

[0067] (v) Preparation of 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole as shown in Formula VI:

[0068] 78.0 g (0.284 mol) of 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole obtained in step (IV), 11.1 g (0.300 mol) of 65% sodium hydride, and 300 mL of toluene were added to a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. 25.0 g (0.318 mol) of chloropropane was added dropwise starting at 20-30 °C. After the addition was complete, the temperature was raised to 40-45 °C, and the reaction was maintained for 6 h. The mixture was then cooled to room temperature, poured into 300 mL of water, and stirred for 30 min. The mixture separated into layers, and the organic phase was washed with water until neutral. Toluene was concentrated to obtain a yellow oily substance, i.e., 89.0 g of the target compound, with a yield of 98.9%; the overall yield was 69.8%.

Claims

1. A method for synthesizing 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole, characterized in that: The chemical equation for the synthesis method is shown below: The preparation steps are as follows: S1: Acylation reaction: 2,4-dichloro-5-aminotrifluorotoluene as shown in formula (I) is reacted with a carboxyl activating agent in the presence of an organic base to give N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide as shown in formula (II); S2: Nitration reaction: The N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide obtained in step S1 reacts with a nitrating agent under the action of concentrated sulfuric acid or fuming sulfuric acid to obtain N-(2,4-dichloro-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in formula (III); S3: Ammonolysis reaction: N-(2,4-dichloro-3-nitro-5-trifluoromethylphenyl)-propionamide obtained in step S2 reacts with ammonia under a certain pressure to obtain N-(2,4-diamino-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in formula (IV); S4: Dehydration cyclization reaction: The N-(2,4-diamino-3-nitro-5-trifluoromethylphenyl)-propionamide obtained in step S3 is cyclized under the action of an acid catalyst to give 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole as shown in formula (V); S5: Alkylation reaction: The 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole obtained in step S4 reacts with an alkylating agent under alkaline catalysis to give the target product as shown in formula (VI).

2. The method for synthesizing 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole according to claim 1, characterized in that: In step S1, the carboxyl activating agent is an acyl halide, an active ester, an active carbon diimide, or an active acyl imidazole; the equivalent amount of the carboxyl activating agent used is 1.0-2.0 times the molar amount of 2,4-dichloro-5-aminotrifluorotoluene shown in formula (I).

3. The method for synthesizing 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole according to claim 1, characterized in that: In step S1, the organic base is trimethylamine, triethylamine, diisopropylethylamine, tributylamine, pyridine, or N,N-dimethylaminopyridine; the amount of organic base used is 1.0-4.0 times the molar amount of 2,4-dichloro-5-aminotrifluorotoluene shown in formula (I).

4. The method for synthesizing 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole according to claim 1, characterized in that: In step S2, the concentrated sulfuric acid has a mass concentration of 98%; the fuming sulfuric acid has a mass concentration of 0-20%; and the amounts of both concentrated sulfuric acid and fuming sulfuric acid are 2.0-20.0 times the molar amount of N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide as shown in formula (II); the nitrating agent is concentrated nitric acid with a mass concentration of 63-97%; and the amount of nitrating agent is 2.0-3.0 times the molar amount of N-(2,4-dichloro-5-trifluoromethylphenyl)-propionamide as shown in formula (II).

5. The method for synthesizing 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole according to claim 1, characterized in that: In step S3, the ammonia is one or a mixture of two of ammonia water or liquid ammonia with a mass concentration of 10-30%, and the amount of ammonia used is 4.0-20.0 times the molar amount of N-(2,4-dichloro-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in formula (III); the reaction pressure is 0.1-2.0 MPa; the reaction temperature is 30-120℃; and the reaction time is 4-30 h.

6. The method for synthesizing 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole according to claim 1, characterized in that: In step S4, the acid catalyst is an organic acid or an inorganic acid; the organic acid is acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, or methanesulfonic acid; the inorganic acid is sulfuric acid, phosphoric acid, or polyphosphoric acid; the amount of acid catalyst used is 2.0-50.0 times the molar amount of N-(2,4-diamino-3-nitro-5-trifluoromethylphenyl)-propionamide as shown in formula (IV).

7. The method for synthesizing 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole according to claim 1, characterized in that: In step S5, the alkylating agent is chloropropane, bromopropane, iodopropane, dipropyl sulfate, or dipropyl carbonate; the amount of the alkylating agent is 1.0-2.0 times the molar amount of 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole as shown in (V).

8. The method for synthesizing 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole according to claim 1, characterized in that: In step S5, the base is an inorganic base, an organic base, or a metal hydride; the inorganic base is sodium carbonate, potassium carbonate, calcium carbonate, calcium oxide, lithium hydroxide, sodium hydroxide, or potassium hydroxide; the organic base is an amine compound or a metal salt of an alcohol, the amine compound is trimethylamine, triethylamine, diisopropylethylamine, tributylamine, pyridine, piperidine, or N,N-dimethylaminopyridine; the metal salt of the alcohol is sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide; the metal hydride is lithium hydride, sodium hydride, potassium hydride, or calcium hydride; the amount of the base catalyst is 1.0-4.0 times the molar amount of 2-ethyl-4-nitro-5-amino-3-H-6-trifluoromethylbenzimidazole as shown in formula (V).

9. The method for synthesizing 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole according to claim 1, characterized in that: The acylation reaction in step S1 is carried out in a solvent at a temperature of -20 to 80°C for 2 to 10 hours. The solvent is one or more of the following: dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, toluene, xylene, tetrahydrofuran, 1,4-dichlorohexane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone. The dehydration cyclization reaction in step S4 is carried out in a solvent at a temperature of 80-180°C for 3-9 hours. The solvent is an organic acid, an inert aromatic solvent, or a polar aprotic solvent. The organic acid is acetic acid, propionic acid, or trifluoroacetic acid. The inert aromatic solvent is toluene, xylene, chlorobenzene, or dichlorobenzene. The polar aprotic solvent is N,N-dimethylformamide, N,N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, hexamethylphosphoric triamine, ethylene glycol dimethyl ether, or diethylene glycol dimethyl ether. The alkylation reaction in step S5 is carried out in a solvent at a temperature of -20 to 180°C for 3 to 8 hours. The solvent is dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, toluene, xylene, tetrahydrofuran, 1,4-dichlorohexacyclohexane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone.

10. A 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole, characterized in that: It is synthesized by the method for synthesizing 1-propyl-2-ethyl-5-trifluoromethyl-6-amino-7-nitrobenzimidazole according to any one of claims 1-9.

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