Chlorfenapyr and synthesis process thereof
By employing a one-pot acylation and cyclization reaction, along with an improved substitution reaction, the problems of large wastewater volume and high cost in brofennig synthesis have been solved, enabling the production of brofennig with high purity and high yield.
Patent Information
- Application Number
- CN202511779821.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-28
- Publication Date
- 2026-01-20
AI Technical Summary
The existing bromonitrile synthesis process suffers from problems such as large wastewater volume, cumbersome steps, large dosage of triethylamine acidifier which is difficult to recover, and high cost.
A one-pot acylation and cyclization reaction was adopted, a new catalyst was used to replace triethylamine, the process was simplified, wastewater discharge was reduced, and the product purity and yield were improved through an improved substitution reaction.
This resulted in reduced wastewater discharge, lower production costs, and improved product purity and overall yield, achieving a yield of 85% and a product purity of 99%.
Abstract
Description
TECHNICAL FIELD
[0001] The present application belongs to the technical field of pesticides, and particularly relates to a chlorfenapyr and a synthesis process thereof. BACKGROUND
[0002] The development of chlorfenapyr is derived from the chemical structure modification of natural antibiotic dioxopirolysin, and a derivative with higher activity and stability is obtained through artificial synthesis. The development aims to solve the resistance problem of traditional insecticides (such as organophosphorus and pyrethroid) and has a broad-spectrum activity on chewing and piercing-sucking pests and mites. Chlorfenapyr is widely used: mainly for crops such as vegetables and fruit trees, to prevent and control pests such as diamondback moth, aphids, mites and termites. The toxicity to mammals is moderate, but the toxicity to aquatic organisms is high, so it needs to be used in a standard way to reduce environmental risk, and the market demand is large.
[0003] At present, the main synthesis route of chlorfenapyr is as follows: p-chlorophenylglycine is used as the main raw material, and acylation reaction is carried out with phosphorus trichloride, trifluoroacetic acid and triethylamine to generate 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazolone through dehydration; then, in the presence of triethylamine, cyclization is carried out with 2-chloroacrylonitrile to generate 2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-nitrile; the generated intermediate is subjected to bromination with bromine to obtain 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-nitrile; and then, substitution reaction is carried out with chloromethyl ether to obtain the product chlorfenapyr after purification. The main problems of the process are as follows: in the acylation reaction and cyclization reaction, a large amount of wastewater is generated, and triethylamine is used in each reaction, which has a large amount, is difficult to recover and has a low recovery rate, resulting in high cost. The previous process is also complicated. In the substitution reaction, triethylamine is also used. Chloromethyl ether is used as a raw material, which has a high purification requirement, so that the industrial purity of chloromethyl ether is about 90%, and low-temperature storage is required. The purity of chloromethyl ether seriously affects the product quality of chlorfenapyr. Chloromethyl ether is a carcinogenic substance. SUMMARY
[0004] The present application aims to provide a chlorfenapyr and a synthesis process thereof. The synthesis process simplifies the process flow, reduces the discharge of wastewater, abandons the use of triethylamine as a deacidifying agent which is not easy to recycle, adopts a new deacidifying agent which is easier to recover and has low loss, reduces the consumption of raw materials, improves the process economy, and has a high total yield of 85% in four-step reactions, so that the purity of the product after beating and purification is more than 99%, which provides a direction for a more economical process, and solves the technical problems of complicated steps, large amount of wastewater, large amount of deacidifying agent triethylamine, difficult recovery, large loss and high production cost in the prior art.
[0005] In order to achieve the above-mentioned purpose, the technical scheme provided by a specific embodiment of the present application is as follows:
[0006] A synthetic process of bromothionate, comprising the following steps:
[0007] One-pot method of acylation and cyclization reaction: acetonitrile is used as a solvent, p-chlorophenyl glycine, trifluoroacetic acid and a catalyst are added and mixed, then phosphorus trichloride is added dropwise, and acylation reaction is carried out by heating; after the acylation reaction is completed, the acetonitrile is removed, a solvent is added for cooling, then 2-chloropropenyl cyanide is added dropwise, an acid binding agent is added, and cyclization reaction is carried out by heating to obtain a reaction solution containing 2-(4-chlorophenyl)-5-trifluoromethyl pyrrole-3-carbonitrile; wherein the catalyst is one or more of N-methyl morpholine, pyridine, pyrrole, N-methyl pyrrole and imidazole;
[0008] Bromination reaction: the reaction solution containing 2-(4-chlorophenyl)-5-trifluoromethyl pyrrole-3-carbonitrile is heated, bromine and hydrogen peroxide are added dropwise for reaction, and after the reaction is completed, an appropriate amount of water is added, and filtration is performed to obtain 4-bromo-2-(4-chlorophenyl)-5-trifluoromethyl pyrrole-3-carbonitrile;
[0009] Substitution reaction: 4-bromo-2-(4-chlorophenyl)-5-trifluoromethyl pyrrole-3-carbonitrile, diethoxymethane, a F acid agent and toluene are mixed, then phosphorus trichloride is added dropwise, and then heating and incubation are performed, and then an appropriate amount of water is added, and the mixture is left to separate into layers; the organic layer is taken, toluene is removed, methanol is added for recrystallization, and then centrifugation is performed to obtain bromothionate.
[0010] In one or more embodiments of the present application, in the acylation reaction, the molar ratio of p-chlorophenyl glycine to acetonitrile is 1:(3-15), the molar ratio of p-chlorophenyl glycine to the catalyst is 1:(0.01-0.1), and the molar ratio of p-chlorophenyl glycine, trifluoroacetic acid and phosphorus trichloride is 1:(1.1-1.6):(1.1-1.6).
[0011] In one or more embodiments of the present application, in the acylation reaction, the mixture of acetonitrile, p-chlorophenyl glycine, trifluoroacetic acid and the catalyst is first warmed to 20-30℃, then phosphorus trichloride is added dropwise, and then the acylation reaction is carried out by heating to 40-80℃, and the reaction time is 5-8h.
[0012] In one or more embodiments of the present application, in the cyclization reaction, the solvent is one or more of N,N-dimethylformamide, acetonitrile, toluene and tetrahydrofuran; and / or,
[0013] In the cyclization reaction, the F acid agent is one or more of diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methyl morpholine and tetramethyl ethylenediamine; and / or,
[0014] The molar ratio of 2-chloropropenyl nitrile, the Friedel-Crafts reagent and p-chlorophenyl glycine in the cyclization reaction is (1.05-1.2):(1-1.3):1, and the molar ratio of the solvent and p-chlorophenyl glycine in the acylation reaction is (5-15):1.
[0015] In one or more embodiments of the present application, in the cyclization reaction, the reaction solution is cooled to 10-20 DEG C by adding a solvent, and after dropwise adding 2-chloropropenyl nitrile and the acid binding agent, the reaction solution is heated to 50-60 DEG C and reacted for 2-4 h.
[0016] In one or more embodiments of the present application, in the bromination reaction, the molar ratio of 2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile, bromine and hydrogen peroxide is 1:(0.55-1.5):(1-2).
[0017] In one or more embodiments of the present application, in the bromination reaction, the reaction temperature is 30-50 DEG C, and the reaction time is 3-4 h.
[0018] In one or more embodiments of the present application, in the substitution reaction, the molar ratio of 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile, diethoxymethane, phosphorus trichloride and the Friedel-Crafts reagent is 1:(1.05-1.4):(1.05-1.3):(1.2-2); and / or,
[0019] In the substitution reaction, the molar ratio of 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile and toluene is 1:(5-10); and / or,
[0020] In the substitution reaction, the Friedel-Crafts reagent is one or more of diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and tetramethylethylenediamine.
[0021] In one or more embodiments of the present application, in the substitution reaction, 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile, diethoxymethane, the Friedel-Crafts reagent and toluene are mixed at 10-20 DEG C, and after dropwise adding phosphorus trichloride, the reaction solution is heated to 40-60 DEG C and kept for 2-4 h.
[0022] Another specific embodiment of the present application provides the technical solution as follows:
[0023] A broflanilide synthesized by the above synthesis process.
[0024] Compared with the prior art, the present application has the following beneficial effects:
[0025] 1. The process of the present application can continuously feed in the acylation and cyclization and bromination, and only one wastewater is discharged in the three-step reaction, thereby greatly reducing the amount of wastewater.
[0026] 2、The process acylation does not use Friedel-Crafts agent compared with traditional process, using catalytic amount of catalyst can save cost.
[0027] 3、The whole process uses new Friedel-Crafts agent instead of triethylamine, avoiding the shortcomings that triethylamine is not easy to separate with water and loss is large, the new Friedel-Crafts agent used in the application is easy to separate with water, and the recovery rate can reach 90%.
[0028] 4、The whole process yield can reach 85%, avoiding complicated steps, reducing consumption and being more economical. DETAILED DESCRIPTION
[0029] In order to enable the personnel in the technical field to better understand the technical solutions in the present disclosure, the technical solutions in the embodiments of the present disclosure are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present disclosure, rather than all the embodiments. Based on the embodiments in the present disclosure, all other embodiments obtained by the personnel in the field without creative labor should belong to the protection scope of the present disclosure.
[0030] A specific embodiment of the present application provides a synthesis process of bromopropylate, comprising the following steps:
[0031] Step 1, one-pot method of acylation and cyclization reaction: acetonitrile is used as a solvent, p-chlorophenyl glycine, trifluoroacetic acid and a catalyst are added and mixed, phosphorus trichloride is added dropwise under temperature control at 20-30℃, and acylation reaction is carried out by heating to 40-80℃, and the time is 5-8h. After the acylation reaction is completed, acetonitrile is removed under reduced pressure, a solvent is added to cool to 10-20℃, then 2-chloropropenyl cyanide is added dropwise and stirred to dissolve, an acid binding agent is added, heated to 50-60℃ to carry out cyclization reaction, the time is 2-4h, and a reaction liquid containing 2-(4-chlorophenyl)-5-trifluoromethyl pyrrole-3-carbonitrile is obtained, which is directly subjected to the next step reaction.
[0032] Specifically, the reaction formula in this step is: , .
[0033] Further, the catalyst is one or more of N-methylmorpholine, pyridine, pyrrole, N-methylpyrrole and imidazole, and the Friedel-Crafts agent is one or more of diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and tetramethylethylenediamine.
[0034] Specifically, the catalyst can preferentially attack the carbonyl carbon of acyl chloride to form an active onium salt intermediate. At this time, the electrophilicity of the acyl carbon is significantly improved, making it more susceptible to ammonium ion (NH4 +The high electrophilicity of the acylpyridinium salt intermediate reduces the activation energy of the attack of the ammonium ion, accelerates the reaction of the acyl chloride and the ammonium, and the catalyst can continuously promote the reaction by recycling (the intermediate can further decompose to regenerate the catalyst), thereby improving the reaction rate and yield.
[0035] Further, in the acylation reaction, the molar ratio of p-chlorophenylglycine to acetonitrile is 1:(3-15), the molar ratio of p-chlorophenylglycine to the catalyst is 1:(0.01-0.1), and the molar ratio of p-chlorophenylglycine, trifluoroacetic acid and phosphorus trichloride is 1:(1.1-1.6):(1.1-1.6).
[0036] Further, in the cyclization reaction, the molar ratio of 2-chloropropenyl cyanide, the Friedel-Crafts agent and p-chlorophenylglycine in the acylation reaction is (1.05-1.2):(1-1.3):1, and the molar ratio of the solvent and p-chlorophenylglycine in the acylation reaction is (5-15):1.
[0037] Step 2, bromination reaction: heat the reaction solution containing 2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile to 30-50°C, and drop bromine and hydrogen peroxide for reaction for 3-4h; after the reaction is completed, add an appropriate amount of water to precipitate the solid, then filter and dry to obtain 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile.
[0038] Specifically, the reaction formula in this step is: .
[0039] Further, the molar ratio of 2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile to bromine, hydrogen peroxide is 1:(0.55-1.5):(1-2).
[0040] Step 3, substitution reaction: mix 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile, diethoxymethane, a Friedel-Crafts agent and toluene, and control the temperature to be 10-20°C; then drop phosphorus trichloride, heat to 40-60°C and keep for 2-4h, add an appropriate amount of water, and stand to separate the layers; take the organic layer, remove toluene under reduced pressure, add methanol, recrystallize, centrifuge, take the precipitate and dry to obtain chlorfenapyr.
[0041] Specifically, the reaction formula in this step is: .
[0042] Further, the molar ratio of 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile, diethoxymethane, phosphorus trichloride and the Friedel-Crafts acid agent is 1: (1.05-1.4): (1.05-1.3): (1.2-2), the molar ratio of 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile and toluene is 1: (5-10), and the Friedel-Crafts acid agent is one or more of diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and tetramethylethylenediamine.
[0043] Another specific embodiment of the present application provides a chlorfenapyr synthesized by the above synthesis process.
[0044] The present application is further described in detail below with reference to specific examples.
[0045] Example 1
[0046] The synthesis process of chlorfenapyr in this example is as follows:
[0047] In a reaction vessel, 10 mol of acetonitrile is added as a solvent, then 1 mol of p-chlorophenylglycine is added, the temperature is controlled at 20-30°C, 1.5 mol of trifluoroacetic acid and 0.05 mol of pyrrole are added, stirred uniformly, 1.1 mol of phosphorus trichloride is added dropwise for acylation reaction, the dropwise addition time is 2-2.5 h, after the dropwise addition is completed, the temperature is raised to 60°C for 6 h of reaction, after the reaction is completed, acetonitrile is removed under reduced pressure, 10 mol of DMF is added to the reaction solution, the temperature is reduced to 10°C, 1.05 mol of 2-chloropropenenitrile is added dropwise, then 1.1 mol of the Friedel-Crafts acid agent diisopropylethylamine is added dropwise for cyclization reaction, after the dropwise addition is completed, the temperature is raised to 60°C for 2 h of reaction, 2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile is obtained.
[0048] The reaction solution of the above step is controlled at 30°C, 0.6 mol of bromine and 1.2 mol of 32% hydrogen peroxide are added dropwise, after the dropwise addition is completed, the reaction is maintained for 3 h, after the reaction is completed, an appropriate amount of water is added, the product is precipitated, the solid is separated and dried, and 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile solid is obtained.
[0049] 1 mol of 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile solid is taken, 5 mol of toluene is added, the temperature is controlled at 10-20°C, 1.1 mol of diethoxymethane and 1.5 mol of the Friedel-Crafts acid agent diisopropylethylamine are added dropwise, the temperature is raised to 40°C, then 1.05 mol of phosphorus trichloride is added dropwise to the reaction solution for substitution reaction, after the dropwise addition is completed, the reaction is maintained for 2 h, water is added for washing, the organic layer is separated after toluene is removed under reduced pressure, 5 mol of methanol is added for recrystallization, centrifugation and drying, and chlorfenapyr is obtained. The content of the final product is 99.2 wt%, and the product yield is 85.3%.
[0050] Example 2
[0051] The synthesis process of the bromothionate in this example is as follows:
[0052] In a reaction vessel, 10 mol of acetonitrile was added as a solvent, and then 1 mol of p-chlorophenylglycine was added. The temperature was controlled at 20-30°C, and then 1.5 mol of trifluoroacetic acid and 0.05 mol of pyridine were added. After stirring, 1.1 mol of phosphorus trichloride was added dropwise for acylation reaction. The dropwise addition was performed for 2-2.5 h, and after the completion of dropwise addition, the temperature was increased to 60°C for 6 h of reaction. After the reaction was completed, acetonitrile was removed under reduced pressure. In the reaction liquid, 10 mol of DMF was added, and the temperature was reduced to 10°C. Then, 1.05 mol of 2-chloropropenyl cyanide was added dropwise, followed by the addition of 1.1 mol of diisopropylethylamine as an acid binding agent for cyclization reaction. After the completion of dropwise addition, the temperature was increased to 60°C for 2 h of reaction, and 2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile was obtained.
[0053] In the reaction liquid of the above step, 0.6 mol of bromine and 1.2 mol of 32% hydrogen peroxide were added dropwise at 30°C. After the completion of dropwise addition, the reaction was maintained for 3 h. After the reaction was completed, an appropriate amount of water was added, and the product was separated and dried to obtain 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile as a solid.
[0054] From 1 mol of 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile solid, 5 mol of toluene was added, and the temperature was controlled at 10-20°C. Then, 1.1 mol of diethoxymethane and 1.5 mol of diisopropylethylamine as an acid binding agent were added dropwise. The temperature was increased to 40°C, and then 1.05 mol of phosphorus trichloride was added dropwise to the reaction liquid for substitution reaction. After the completion of dropwise addition, the reaction was maintained for 2 h, and then water was added for washing. After the organic layer was separated and the toluene was removed under reduced pressure, 5 mol of methanol was added for recrystallization. After centrifugation and drying, bromothionate was obtained. The content of the final product was 99.1 wt%, and the yield of the product was 84.1%.
[0055] Example 3
[0056] The synthesis process of the bromothionate in this example is as follows:
[0057] In the reaction vessel, 10 mol of acetonitrile was added as a solvent, 1 mol of p-chlorophenylglycine was added, the temperature was controlled at 20-30°C, 1.5 mol of trifluoroacetic acid and 0.05 mol of N-methylpyrrole were added, stirring was uniform, 1.1 mol of phosphorus trichloride was added dropwise for acylation reaction, the dropwise addition time was 2-2.5 h, after the dropwise addition was completed, the temperature was increased to 60°C and the reaction was maintained for 6 h, after the reaction was completed, acetonitrile was removed under reduced pressure, 10 mol of DMF was added to the reaction liquid, the temperature was reduced to 10°C, 1.05 mol of 2-chloropropenenitrile was added dropwise, after the dropwise addition was completed, 1.1 mol of the Friedel-Crafts agent diisopropylethylamine was added for cyclization reaction, after the dropwise addition was completed, the temperature was increased to 60°C and the reaction was maintained for 2 h, 2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile was obtained.
[0058] The reaction liquid of the above step was controlled at 30°C, 0.6 mol of bromine and 1.2 mol of 32% hydrogen peroxide were added dropwise, after the dropwise addition was completed, the reaction was maintained for 3 h, after the reaction was completed, an appropriate amount of water was added, the product was precipitated, the solid was separated and dried, and 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile solid was obtained.
[0059] 1 mol of 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile solid was taken, 5 mol of toluene was added, the temperature was controlled at 10-20°C, 1.1 mol of diethoxymethane and 1.5 mol of the acid-binding agent diisopropylethylamine were added dropwise, the temperature was increased to 40°C, 1.05 mol of phosphorus trichloride was added dropwise to the reaction liquid for substitution reaction, after the dropwise addition was completed, the reaction was maintained for 2 h, water was added and washed, the organic layer was removed under reduced pressure after toluene was removed, 5 mol of methanol was added for recrystallization, centrifugation was performed, and bromothionyl was dried, the product yield was 71.8%.
[0060] Example 4
[0061] The synthesis process of bromothionyl in this example is as follows:
[0062] In the reaction vessel, 15 mol of acetonitrile was added as a solvent, 1 mol of p-chlorophenylglycine was added, the temperature was controlled at 20-30°C, 1.6 mol of trifluoroacetic acid and 0.05 mol of N-methylmorpholine were added, stirring was uniform, 1.2 mol of phosphorus trichloride was added dropwise for acylation reaction, the dropwise addition time was 3-4 h, after the dropwise addition was completed, the temperature was increased to 70°C and the reaction was maintained for 6 h, after the reaction was completed, acetonitrile was removed under reduced pressure, 10 mol of toluene was added to the reaction liquid, the temperature was reduced to 10°C, 1.1 mol of 2-chloropropenenitrile was added dropwise, after the dropwise addition was completed, 1.2 mol of the Friedel-Crafts agent 4-dimethylaminopyridine was added for cyclization reaction, after the dropwise addition was completed, the temperature was increased to 60°C and the reaction was maintained for 3 h, 2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile was obtained.
[0063] The reaction solution was controlled at 40°C, 0.7 mol of bromine and 1.1 mol of 32% hydrogen peroxide were added dropwise, and after the dropwise addition was completed, the reaction was maintained for 4 h. After the reaction was completed, an appropriate amount of water was added, the product was precipitated, the solid was separated and dried, and 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile solid was obtained.
[0064] 1 mol of 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile solid was taken, 5 mol of toluene was added, and the temperature was controlled at 10-20°C. 1.1 mol of diethoxymethane and 1.5 mol of acid binding agent 4-dimethylaminopyridine were added dropwise, the temperature was raised to 40°C, and then 1.1 mol of phosphorus trichloride was added dropwise to the reaction solution for substitution reaction. After the dropwise addition was completed, the reaction was maintained for 3 h, water was added for washing, and the organic layer was separated after the toluene was removed under reduced pressure. Then, 10 mol of methanol was added for recrystallization, centrifugation, and drying to obtain bromothionyl. The content of the final product was 99.4 wt%, and the yield of the product was 83.2%.
[0065] Example 5
[0066] The synthesis process of bromothionyl in this example is as follows:
[0067] In a reaction vessel, 12 mol of acetonitrile was added as a solvent, 1 mol of p-chlorophenylglycine was added, the temperature was controlled at 20-30°C, 1.2 mol of trifluoroacetic acid and 0.1 mol of imidazole were added, and the mixture was stirred uniformly. Then, 1.1 mol of phosphorus trichloride was added dropwise for acylation reaction. The dropwise addition was completed in 3-4 h, the temperature was raised to 70°C, and the reaction was maintained for 8 h. After the reaction was completed, the acetonitrile was removed under reduced pressure, 15 mol of acetonitrile was added to the reaction solution, the temperature was reduced to 10°C, 1.2 mol of 2-chloropropenyl cyanide was added dropwise, and then 1.3 mol of acid binding agent tetramethyl ethylenediamine was added for cyclization reaction. After the dropwise addition was completed, the temperature was raised to 60°C, and the reaction was maintained for 4 h to obtain 2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile.
[0068] The reaction solution was controlled at 50°C, 0.7 mol of bromine and 1.1 mol of 32% hydrogen peroxide were added dropwise, and after the dropwise addition was completed, the reaction was maintained for 4 h. After the reaction was completed, an appropriate amount of water was added, the product was precipitated, the solid was separated and dried, and 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile solid was obtained.
[0069] Take 1 mol 4-bromo-2-(4-chlorophenyl)-5-trifluoromethyl pyrrole-3-carbonitrile solid, add 10 mol toluene, control temperature at 10-20℃, drop 1.2 mol diethoxymethane and 1.3 mol acid binding agent tetramethyl ethylenediamine, warm up to 40℃, then drop 1.2 mol phosphorus trichloride into the reaction solution for substitution reaction, after drop completion, keep warm for 3h, add water for washing, stand for layering, after removing toluene from organic layer under reduced pressure, add 15 mol methanol for recrystallization, centrifuge, dry, get bromothiophene. The final product content is 99.4wt%, the product yield is 84.6%.
[0070] It is apparent to those skilled in the art that the present disclosure is not limited to the details of the foregoing exemplary embodiments, and that the present disclosure can be implemented in other particular forms without departing from the spirit or essential characteristics of the present disclosure. Therefore, the embodiments should be considered in all respects as illustrative and not restrictive, the scope of the present disclosure being defined by the appended claims rather than the foregoing description, and it is intended that all changes which come within the meaning and range of equivalency of the claims are resolvable as being within the scope of the present disclosure.
[0071] In addition, it should be understood that although the present specification is described in terms of embodiments, not every embodiment contains only one independent technical solution, and the description of the specification is only for the sake of clarity, and those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that those skilled in the art can understand.
Claims
1. A process for the synthesis of bromopropylate, characterized in that, The synthesis process of the bromothionol comprises the following steps: One-pot method of acylation and cyclization reaction: acetonitrile is used as a solvent, p-chlorophenylglycine, trifluoroacetic acid and a catalyst are added and mixed, then phosphorus trichloride is added dropwise, and acylation reaction is carried out by heating; after the acylation reaction is completed, the acetonitrile is removed, a solvent is added to reduce the temperature, then 2-chloroacrylonitrile is added dropwise, a deacidifying agent is added, and cyclization reaction is carried out by heating to obtain a reaction solution containing 2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile; wherein the catalyst is one or more of N-methylmorpholine, pyridine, pyrrole, N-methylpyrrole and imidazole; Bromination reaction: the reaction solution containing 2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile is heated, bromine and hydrogen peroxide are added dropwise for reaction, and then an appropriate amount of water is added after the reaction is completed, and filtration is performed to obtain 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile; Substitution reaction: 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile, diethoxymethane, a deacidifying agent and toluene are mixed, phosphorus trichloride is added dropwise, then heating and insulation are carried out, an appropriate amount of water is added, and then separation is carried out after standing; the organic layer is taken, toluene is removed, methanol is added for recrystallization, then centrifugation is carried out to obtain bromothionol.
2. The process for synthesis of bromopropylate according to claim 1, wherein, In the acylation reaction, the molar ratio of p-chlorophenylglycine to acetonitrile is 1:(3-15), the molar ratio of p-chlorophenylglycine to the catalyst is 1:(0.01-0.1), and the molar ratio of p-chlorophenylglycine, trifluoroacetic acid and phosphorus trichloride is 1:(1.1-1.6):(1.1-1.6).
3. The process for synthesis of bromopropylate as claimed in claim 1 wherein, In the acylation reaction, the mixture of acetonitrile, p-chlorophenylglycine, trifluoroacetic acid and the catalyst is first heated to 20-30°C, then phosphorus trichloride is added dropwise, and then the acylation reaction is carried out by heating to 40-80°C, and the reaction time is 5-8h.
4. The process for synthesis of bromopropylate as claimed in claim 1 wherein, In the cyclization reaction, the solvent is one or more of N,N-dimethylformamide, acetonitrile, toluene and tetrahydrofuran; and / or, In the cyclization reaction, the deacidifying agent is one or more of diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and tetramethylethylenediamine; and / or, In the cyclization reaction, the molar ratio of 2-chloroacrylonitrile, the deacidifying agent and p-chlorophenylglycine in the acylation reaction is (1.05-1.2):(1-1.3):1, and the molar ratio of the solvent and p-chlorophenylglycine in the acylation reaction is (5-15):
1.
5. The process for synthesis of bromopropylate as claimed in claim 1 wherein, In the cyclization reaction, the reaction solution is cooled to 10-20°C by adding a solvent, 2-chloroacrylonitrile and the deacidifying agent are added dropwise, and then the reaction is carried out by heating to 50-60°C for 2-4h.
6. The process for synthesis of bromopropylate as claimed in claim 1, wherein, In the bromination reaction, the molar ratio of 2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile, bromine and hydrogen peroxide is 1:(0.55-1.5):(1-2).
7. The process for synthesis of bromopropylate as claimed in claim 1, wherein, In the bromination reaction, the reaction temperature is 30-50°C, and the reaction time is 3-4h.
8. The process for synthesis of bromopropylate as claimed in claim 1, wherein, In the substitution reaction, the molar ratio of 4-bromo-2-(4-chlorophenyl)-5- trifluoromethylpyrrole-3-carbonitrile, diethoxymethane, phosphorus trichloride and the Friedel-Crafts reagent is 1:(1.05-1.4):(1.05-1.3):(1.2-2); and / or, In the substitution reaction, the molar ratio of 4-bromo-2-(4-chlorophenyl)-5- trifluoromethylpyrrole-3-carbonitrile and toluene is 1:(5-10); and / or, In the substitution reaction, the Friedel-Crafts reagent is one or more of diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, tetramethylethylenediamine.
9. The process for synthesis of bromopropylate as claimed in claim 1 wherein, In the substitution reaction, 4-bromo-2-(4-chlorophenyl)-5-trifluoromethylpyrrole-3- carbonitrile, diethoxymethane, the Friedel-Crafts reagent and toluene are mixed at 10-20°C, and after dropwise addition of phosphorus trichloride, heating is carried out to 40-60°C for 2-4h.
10. A bromopropylate characterized in that, The chlorfenapyr is synthesized by the synthetic process of claim 1.