Preparation method of bromo-pyrrole nitrile

Abstract

The invention relates to the technical field of organic synthesis, and discloses a preparation method of bromo-pyrrole nitrile. The method comprises the following steps: (1) mixing p-chlorophenylglycine, acetonitrile, trifluoroacetic acid and a catalyst, then dropwise adding acyl chloride and carrying out acylation reaction, and after the reaction is completed, purging with an inert gas; (2) under the inert gas, mixing the mixture obtained in the step (1) with inorganic salt, then dropwise adding 2-chloroacrylonitrile, carrying out cyclization reaction, and separating a liquid phase from the obtained mixture; and (3) under the inert gas, mixing the liquid phase obtained in the step (2), hydrobromic acid and hydrogen peroxide, carrying out a bromination reaction, then extracting with acetonitrile to obtain an acetonitrile layer, then removing the acetonitrile, and then carrying out cooling crystallization to obtain the bromo-pyrrolenitrile. According to the technical scheme, the reaction yield is high, different solvents do not need to be frequently replaced, and the solvents can be recycled.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing bromopyrrole carbonitrile. Background Art

[0002] Bromopyrrole nitrile can be used in non-metallic marine antifouling coatings and ship antifouling coatings. It is a metal-free antifouling agent for use on ship hulls and other marine structures. It exhibits broad activity against both hard-shelled and soft-bodied invertebrate fouling organisms. Due to its chemical and physical stability, low water solubility, and leaching properties, it is suitable for use in various antifouling coatings, including traditional rosin-based controlled loss polymer (CDP) coatings and self-polishing copolymer (SPC) systems. It offers advantages such as being a metal-free antifouling agent; providing a cost-effective alternative to copper-based anti-odor agents at low concentrations; broad-spectrum control of hard-fouling microorganisms; compatibility with marine and freshwater environments; and rapid decomposition in aquatic environments. Bromopyrrole nitrile is also an important intermediate in the production of the insecticide chlorfenapyr, a novel heterocyclic insecticide, acaricide, and nematicide. Chlorfenapyr itself is non-toxic to insects, targeting the mitochondria in insects. Its unique mechanism of action, broad spectrum of insecticides and acaricides, and low toxicity and high efficacy have led to its increasing popularity.

[0003] Currently, industrial production of bromopyrrole carbonitrile mainly uses p-chlorophthalic anhydride as the starting material and synthesizes the product in three steps. However, these steps involve the replacement of different solvents, water washing, and multiple solvent evaporation, resulting in high solvent consumption. Phosphorus trichloride is also used, and phosphorus-containing wastewater is difficult to treat. The acid-binding agent triethylamine is used, and the recovery of triethylamine produces a large amount of alkaline wastewater with a high nitrogen content, and the triethylamine recovery rate is low. The use of DMF as a solvent produces a large amount of DMF with a high water content, which cannot be directly reused. DMF is also difficult to recycle, has high recycling costs, and is environmentally unfriendly. Summary of the Invention

[0004] The present invention aims to overcome the environmentally unfriendly problems existing in the prior art, such as the generation of difficult-to-treat phosphorus-containing wastewater when using phosphorus trichloride, the generation of a large amount of alkaline wastewater with a high nitrogen content and a low triethylamine recovery rate when using triethylamine as an acid-binding agent, and the generation of a large amount of DMF with a high water content that cannot be directly reused, the difficulty in recovering DMF, and the high cost of recovery when using DMF as a solvent. A method for preparing bromopyrrole carbonitrile is provided. The technical solution uses only acetonitrile as a solvent, replaces phosphorus trichloride with acyl chloride, and replaces the organic acid-binding agent (such as triethylamine) in the existing process with an inorganic salt acid-binding agent. This method effectively solves the tedious operations of changing different solvents and washing with water, and eliminates the need to recover environmentally unfriendly raw materials such as triethylamine and DMF.

[0005] In order to achieve the above object, the present invention provides a method for preparing bromopyrrole carbonitrile, which comprises the following steps: (1) p-Chlorophenylglycine, acetonitrile, trifluoroacetic acid and a catalyst are mixed, followed by dropwise addition of acyl chloride to carry out an acylation reaction, and after completion of the reaction, the mixture is purged with an inert gas; (2) mixing the mixture obtained in step (1) and an inorganic salt under the inert gas, then adding 2-chloroacrylonitrile dropwise and performing a cyclization reaction, and separating a liquid phase from the obtained mixture; (3) Under the inert gas, the liquid phase obtained in step (2), hydrobromic acid and hydrogen peroxide are mixed and subjected to bromination reaction, followed by extraction with acetonitrile to obtain an acetonitrile layer, followed by desolvation of the acetonitrile, and then cooling and crystallization to obtain bromopyrrole carbonitrile.

[0006] Preferably, in step (1), the mass ratio of the p-chlorophenylglycine to the acetonitrile is 1:(2-6).

[0007] Preferably, in step (1), the molar ratio of the p-chlorophenylglycine to the trifluoroacetic acid is 1:(1-1.1).

[0008] Preferably, in step (1), the acyl chloride is thionyl chloride and / or oxalyl chloride.

[0009] Preferably, the molar ratio of the p-chlorophenylglycine to the acyl chloride is 1:(1-1.2).

[0010] Preferably, in step (1), the temperature is controlled to be -10 to 20°C when the acid chloride is added dropwise.

[0011] Preferably, in step (1), the conditions of the acylation reaction include: temperature of -10 to 20°C, and time of 1 to 3 hours.

[0012] Preferably, in step (1), the catalyst is an organic weak base, preferably triethylamine and / or DMF.

[0013] Preferably, in step (1), the mass ratio of the catalyst to the p-chlorophenylglycine is 0.1%-3%.

[0014] Preferably, in step (2), the inorganic salt is an alkaline inorganic salt, preferably at least one of sodium bicarbonate, sodium carbonate and potassium bicarbonate.

[0015] Preferably, the molar ratio of the inorganic salt to the p-chlorophenylglycine is 1:(1-1.5).

[0016] Preferably, in step (2), the molar ratio of the p-chlorophenylglycine to the 2-chloroacrylonitrile is 1:(1-1.2).

[0017] Preferably, in step (2), the temperature is controlled to be 10-40°C when 2-chloroacrylonitrile is added dropwise.

[0018] Preferably, in step (2), the conditions of the cyclization reaction include: temperature of 10-40° C. and time of 2-4 h.

[0019] Preferably, in step (3), the molar ratio of the p-chlorophenylglycine to the hydrobromic acid is 1:(1-1.1).

[0020] Preferably, in step (3), the mass ratio of the hydrobromic acid to the hydrogen peroxide is (0.7-1):1.

[0021] Preferably, in step (3), the conditions of the bromination reaction include: temperature of 10-40° C. and time of 2-4 h.

[0022] Preferably, in step (3), when the volume of the acetonitrile removed by desolvation is 40%-70% of the volume when added, cooling crystallization is performed.

[0023] Preferably, the temperature of the cooling crystallization is -15 to 5°C.

[0024] Preferably, the method further comprises: after the cooling crystallization, performing solid-liquid separation, distilling off the acetonitrile in the obtained liquid phase, and combining the distilled acetonitrile with the acetonitrile desolvated from the acetonitrile layer and reusing the combined acetonitrile in step (1).

[0025] Compared with the prior art, the present invention has the following technical effects: (1) The preparation method of bromopyrrole carbonitrile of the present invention has a short process step, cheap reaction raw materials, milder process conditions, and is more suitable for process production; (2) The method for preparing bromopyrrole carbonitrile of the present invention has high reaction yield, good product quality, good selectivity, and good competitive advantages; (3) The preparation method of bromopyrrole carbonitrile of the present invention uses only acetonitrile as a solvent, replaces phosphorus trichloride with acyl chloride, and replaces the organic acid binding agent (such as triethylamine, etc.) in the existing process with an inorganic salt acid binding agent, thereby effectively solving the tedious operation of changing different solvents and washing with water, and eliminating the need to recycle environmentally unfriendly raw materials such as triethylamine and DMF. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The present invention is a synthetic flow chart of the method for preparing bromopyrrole carbonitrile. DETAILED DESCRIPTION

[0027] The following is a detailed description of the specific embodiments of the present invention. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention and are not intended to limit the present invention.

[0028] The endpoints of the ranges and any values disclosed herein are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0029] like Figure 1 As shown, the preparation method of bromopyrrole carbonitrile of the present invention comprises the following steps: (1) p-Chlorophenylglycine, acetonitrile, trifluoroacetic acid and a catalyst are mixed, followed by dropwise addition of acyl chloride to carry out an acylation reaction, and after completion of the reaction, the mixture is purged with an inert gas; (2) mixing the mixture obtained in step (1) and an inorganic salt under the inert gas, then adding 2-chloroacrylonitrile dropwise and performing a cyclization reaction, and separating a liquid phase from the obtained mixture; (3) Under the inert gas, the liquid phase obtained in step (2), hydrobromic acid and hydrogen peroxide are mixed and subjected to bromination reaction, followed by extraction with acetonitrile to obtain an acetonitrile layer, followed by desolvation of the acetonitrile, and then cooling and crystallization to obtain bromopyrrole carbonitrile.

[0030] The method of the present invention has fewer synthesis steps, cheaper reaction raw materials, milder process conditions, and is more suitable for industrial production. In addition, only acetonitrile is used as a solvent, phosphorus trichloride is replaced by acyl chloride, and organic acid binders (such as triethylamine) in existing processes are replaced by inorganic salt acid binders, effectively eliminating the tedious operations of changing different solvents and washing with water, and eliminating the need to recycle environmentally unfriendly raw materials such as triethylamine and DMF. Furthermore, the method has high reaction yield, good product quality, and good selectivity, thus having a good competitive advantage.

[0031] In the method of the present invention, in step (1), the mass ratio of the amount of the p-chlorophenylglycine to the acetonitrile can be 1:(2-6), preferably 1:(44-5), and specifically can be 1:2, 1:3, 1:4, 1:5 or 1:6.

[0032] In the method of the present invention, in step (1), the molar ratio of the p-chlorophenylglycine to the trifluoroacetic acid can be 1:(1-1.1), preferably 1:(1.02-1.05), and specifically can be 1:1, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09 or 1:1.1.

[0033] In the method of the present invention, in step (1), in order to improve the product yield, the acyl chloride is preferably thionyl chloride and / or oxalyl chloride, more preferably oxalyl chloride. The molar ratio of the p-chlorophenylglycine to the acyl chloride can be 1:(1-1.2), preferably 1:(1.05-1.1), and specifically can be 1:1, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09, 1:1.1, 1:1.12, 1:1.14, 1:1.16, 1:1.18 or 1:1.2.

[0034] In the method of the present invention, in step (1), the catalyst may be an organic weak base, preferably triethylamine and / or DMF, more preferably DMF. In step (1), the mass ratio of the catalyst to the p-chlorophenylglycine may be 0.1%-3%, preferably 0.5%-1%.

[0035] In the method of the present invention, in step (1), the temperature can be controlled at -10 to 20°C, preferably 0-5°C, when the acid chloride is added dropwise. In step (1), the conditions of the acylation reaction include: the temperature can be -10 to 20°C, preferably 0-5°C; the time can be 1-3 hours, preferably 2-3 hours. In step (1), after it is detected that the p-chlorophenylglycine is completely reacted, it is purged with an inert gas. The inert gas can be at least one of nitrogen, helium and argon, preferably nitrogen. Preferably, the purity of the nitrogen is 99.0wt%-99.9wt%.

[0036] In the method of the present invention, in step (2), the inorganic salt may be an alkaline inorganic salt, preferably at least one of sodium bicarbonate, sodium carbonate, and potassium bicarbonate, more preferably sodium bicarbonate. The molar ratio of the inorganic salt to the p-chlorophenylglycine may be 1:(1-1.5), preferably 1:(1.1-1.3), specifically, for example, 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, or 1:1.5.

[0037] In the method of the present invention, in step (2), the molar ratio of the amount of p-chlorophenylglycine to the amount of 2-chloroacrylonitrile can be 1:(1-1.2), preferably 1:(1.02-1.1), specifically, for example, 1:1, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09, 1:1.1, 1:1.12, 1:1.14, 1:1.16, 1:1.18 or 1:1.2. In step (2), the temperature can be controlled at 10-40°C, preferably 20-25°C when 2-chloroacrylonitrile is added dropwise. In step (2), the conditions of the cyclization reaction include: the temperature can be 10-40°C, preferably 20-25°C; the time can be 2-4h, preferably 3-4h. In step (2), after it is detected that the product obtained in step (1) has completely reacted, a liquid phase is separated from the obtained mixture by filtration, and the liquid phase is transferred to a reaction flask. The cyclization reaction can be carried out in an inert gas.

[0038] In the method of the present invention, in step (3), the molar ratio of the amount of the p-chlorophenylglycine to the amount of the hydrobromic acid can be 1: (1-1.1), preferably 1: (1.02-1.05), specifically for example, 1: 1, 1: 1.01, 1: 1.02, 1: 1.03, 1: 1.04, 1: 1.05, 1: 1.06, 1: 1.07, 1: 1.08, 1: 1.09 or 1: 1.1. The concentration of the hydrobromic acid can be 40 wt%-60 wt%, preferably 45 wt%-55 wt%. The hydrogen peroxide can be 25 wt%-40 wt%, preferably 25 wt%-35 wt%. The mass ratio of the amount of the hydrobromic acid to the amount of the hydrogen peroxide can be (0.7-1): 1, preferably (0.8-0.86): 1.

[0039] In the method of the present invention, in step (3), the conditions of the bromination reaction include: a temperature of 10-40°C, preferably 20-25°C; and a time of 2-4 hours, preferably 3-4 hours. In step (3), after it is detected that the product obtained in step (2) has completely reacted, the resulting mixture is allowed to stand for 25-40 minutes, and the layers are separated to obtain an aqueous layer. The aqueous layer is extracted with acetonitrile, and the acetonitrile layer obtained by extraction and the acetonitrile layer obtained by separation are mixed, and then the acetonitrile is evaporated to remove the acetonitrile. The evaporation temperature can be 40-90°C, preferably 50-80°C. The bromination reaction can be carried out in an inert gas.

[0040] In the method of the present invention, in step (3), when the volume of the acetonitrile removed by desolvation is 40%-70%, preferably 50%-60%, of the volume at the time of addition, cooling crystallization is performed. The temperature of the cooling crystallization can be -15 to 5°C, preferably -5 to 0°C. The method may further include: after the cooling crystallization, performing solid-liquid separation by suction filtration, and drying the obtained solid product at a temperature of 30-50°C for 2-10 hours.

[0041] In the method of the present invention, the method may further include: after the cooling crystallization, performing solid-liquid separation by suction filtration, distilling off the acetonitrile in the obtained liquid phase, and combining the distilled acetonitrile with the acetonitrile desolvated from the acetonitrile layer and then reusing it in step (1). The method may further include: combining the distilled acetonitrile with the acetonitrile desolvated from the acetonitrile layer and then drying it. The drying may be performed using anhydrous sodium sulfate.

[0042] In some embodiments, as Figure 1 As shown, the present invention provides a method for preparing bromopyrrole carbonitrile comprising the following steps: (1) p-Chlorophenylglycine, acetonitrile, trifluoroacetic acid and a catalyst are mixed, and then acid chloride is added dropwise at a temperature of -10 to 20°C, and then an acylation reaction is carried out at a temperature of -10 to 20°C for 1-3 hours. When it is detected that the p-chlorophenylglycine is completely reacted, it is purged with an inert gas, wherein the mass ratio of the p-chlorophenylglycine to the acetonitrile is 1:(2-6), the molar ratio of the p-chlorophenylglycine to the trifluoroacetic acid is 1:(1-1.1), the molar ratio of the p-chlorophenylglycine to the acid chloride is 1:(1-1.2), and the mass ratio of the catalyst to the p-chlorophenylglycine is 0.1%-3%; (2) under the inert gas, the mixture obtained in step (1) and the inorganic salt are mixed, and then 2-chloroacrylonitrile is added dropwise at a temperature of 10-40° C. and a cyclization reaction is carried out at a temperature of 10-40° C. for 2-4 hours. When it is detected that the product obtained in step (1) is completely reacted, the liquid phase is separated from the obtained mixture by filtration, wherein the molar ratio of the inorganic salt to the p-chlorophenylglycine is 1:(1-1.5), and the molar ratio of the p-chlorophenylglycine to the 2-chloroacrylonitrile is 1:(1-1.2); (3) Under the inert gas, the liquid phase obtained in step (2), hydrobromic acid and hydrogen peroxide are mixed and bromination reaction is carried out at a temperature of 10-40 ° C for 2-4 hours. When it is detected that the product obtained in step (2) is completely reacted, the obtained mixture is allowed to stand for 25-40 minutes, and the aqueous layer is separated and the aqueous layer is extracted with acetonitrile. The acetonitrile layer obtained by extraction and the acetonitrile layer obtained by separation are mixed, and then the acetonitrile is evaporated and desolvated at a temperature of 40-90 ° C., and then when the volume of the desolvated acetonitrile is 40%-70% of the volume at the time of addition, the temperature is lowered to a temperature of -15 to 5 ° C for crystallization, and filtered into The solid-liquid separation is carried out, and the obtained solid product is dried at a temperature of 30-50° C. for 2-10 hours to obtain bromopyrrole carbonitrile. The acetonitrile in the obtained liquid phase is evaporated, and the evaporated acetonitrile is combined with the acetonitrile desolvated from the acetonitrile layer and dried over anhydrous sodium sulfate, and then reused in step (1), wherein the molar ratio of the amount of the p-chlorophenylglycine to the amount of the hydrobromic acid is 1: (1-1.1), the concentration of the hydrobromic acid is 40wt%-60wt%, the amount of the hydrogen peroxide is 25wt%-40wt%, and the mass ratio of the amount of the hydrobromic acid to the amount of the hydrogen peroxide is (0.7-1): 1.

[0043] In other embodiments, Figure 1 As shown, the present invention provides a method for preparing bromopyrrole carbonitrile comprising the following steps: (1) p-Chlorophenylglycine, acetonitrile, trifluoroacetic acid and a catalyst are mixed, and then acid chloride is added dropwise at a temperature of 0-5°C, and then an acylation reaction is carried out at a temperature of 0-5°C for 2-3 hours. When it is detected that the p-chlorophenylglycine is completely reacted, it is purged with an inert gas, wherein the mass ratio of the p-chlorophenylglycine to the acetonitrile is 1:(4-5), the molar ratio of the p-chlorophenylglycine to the trifluoroacetic acid is 1:(1.02-1.05), the molar ratio of the p-chlorophenylglycine to the acid chloride is 1:(1.05-1.1), and the mass ratio of the catalyst to the p-chlorophenylglycine is 0.5%-1%; (2) under the inert gas, the mixture obtained in step (1) and the inorganic salt are mixed, and then 2-chloroacrylonitrile is added dropwise at a temperature of 20-25° C. and a cyclization reaction is carried out at a temperature of 20-25° C. for 3-4 hours. When it is detected that the product obtained in step (1) is completely reacted, the liquid phase is separated from the obtained mixture by filtration, wherein the molar ratio of the inorganic salt to the p-chlorophenylglycine is 1:(1.1-1.3), and the molar ratio of the p-chlorophenylglycine to the 2-chloroacrylonitrile is 1:(1.02-1.1); (3) Under the inert gas, the liquid phase obtained in step (2), hydrobromic acid and hydrogen peroxide are mixed and bromination reaction is carried out at a temperature of 20-25 ° C for 3-4 hours. When it is detected that the product obtained in step (2) is completely reacted, the obtained mixture is allowed to stand for 25-40 minutes, and the aqueous layer is separated and the aqueous layer is extracted with acetonitrile. The acetonitrile layer obtained by extraction and the acetonitrile layer obtained by separation are mixed, and then the acetonitrile is evaporated and desolvated at a temperature of 50-80 ° C., and then when the volume of the desolvated acetonitrile is 50%-60% of the volume at the time of addition, the temperature is lowered to a temperature of -5 to 0 ° C for crystallization, and solid-liquid separation is carried out by suction filtration. The obtained solid product is dried at a temperature of 30-50° C. for 2-10 h to obtain bromopyrrole carbonitrile, the acetonitrile in the obtained liquid phase is evaporated, and the evaporated acetonitrile is combined with the acetonitrile desolvated from the acetonitrile layer and dried over anhydrous sodium sulfate, and then reused in step (1), wherein the molar ratio of the amount of the p-chlorophenylglycine to the amount of the hydrobromic acid is 1: (1.02-1.05), the concentration of the hydrobromic acid is 45wt%-55wt%, the amount of the hydrogen peroxide is 25wt%-35wt%, and the mass ratio of the amount of the hydrobromic acid to the amount of the hydrogen peroxide is (0.8-0.86): 1.

[0044] The following examples further illustrate the preparation method of the bromopyrrole carbonitrile of the present invention. The examples are implemented based on the technical solution of the present invention, and provide detailed implementation methods and specific operating processes, but the scope of protection of the present invention is not limited to the following examples.

[0045] The experimental methods in the following examples, unless otherwise specified, are all conventional methods in the art. The experimental materials used in the following examples, unless otherwise specified, are all commercially available.

[0046] Example 1 (1) In a 2 L reaction vessel, 185.6 g of p-chlorophenylglycine, 742 g of acetonitrile, 116.3 g of trifluoroacetic acid, and 0.93 g of DMF were mixed, and then 133.3 g of oxalyl chloride was added dropwise at 0°C. The acylation reaction was then carried out at 0°C for 2 h. When the p-chlorophenylglycine was detected to be completely reacted, the reaction was purged with nitrogen. (2) Under nitrogen, 92.4 g of sodium bicarbonate was added to the mixture obtained in step (1) and mixed, and then 89.26 g of 2-chloroacrylonitrile was added dropwise at a temperature of 25° C., followed by a cyclization reaction at 25° C. for 3 h. When it was detected that the product obtained in step (1) had completely reacted, the liquid phase was separated from the obtained mixture by filtration and transferred to a reaction vessel; (3) Under nitrogen, the liquid phase obtained in step (2), 172 g of hydrobromic acid with a concentration of 48 wt % and 200 g of hydrogen peroxide with a concentration of 30 wt % were mixed and bromination reaction was carried out at a temperature of 25° C. for 3 h. When it was detected that the product obtained in step (2) was completely reacted, the obtained mixture was allowed to stand for 30 min, and the aqueous layer was obtained by separation. The aqueous layer was extracted with 80 g of acetonitrile. The acetonitrile layer obtained by extraction and the acetonitrile layer obtained by separation were mixed, and then 493 g of acetonitrile was evaporated and desolvated at a temperature of 60° C., and the temperature was lowered to 0° C. for crystallization. The solid-liquid separation was carried out by suction filtration. The obtained solid product was dried at a temperature of 40° C. for 6 h to obtain 360 g of bromopyrrolecarbonitrile, and the yield was measured to be 95.9%. The acetonitrile in the obtained liquid phase was evaporated, and the evaporated acetonitrile was combined with the acetonitrile desolvated from the acetonitrile layer and dried over anhydrous sodium sulfate, and then returned to step (1).

[0047] Example 2 (1) In a 2 L reaction vessel, 185.6 g of p-chlorophenylglycine, 928 g of acetonitrile, 120 g of trifluoroacetic acid, and 1.86 g of DMF were mixed, and then 139.6 g of oxalyl chloride was added dropwise while controlling the temperature at 5°C. The acylation reaction was then carried out at 5°C for 3 h. When the p-chlorophenylglycine was detected to be completely reacted, the reaction was purged with nitrogen. (2) Under nitrogen, 109 g of sodium bicarbonate was added to the mixture obtained in step (1) and mixed, and then 96.25 g of 2-chloroacrylonitrile was added dropwise at a temperature of 20° C. and a cyclization reaction was carried out at a temperature of 20° C. for 4 h. When it was detected that the product obtained in step (1) was completely reacted, the liquid phase was separated from the obtained mixture by filtration and transferred to a reaction vessel; (3) Under nitrogen, the liquid phase obtained in step (2), 177 g of hydrobromic acid with a concentration of 48 wt % and 221 g of hydrogen peroxide with a concentration of 30 wt % were mixed and bromination reaction was carried out at a temperature of 20° C. for 4 h. When it was detected that the product obtained in step (2) was completely reacted, the obtained mixture was allowed to stand for 30 min, and the aqueous layer was separated by stratification. The aqueous layer was extracted with 80 g of acetonitrile. The acetonitrile layer obtained by extraction and the acetonitrile layer obtained by stratification were mixed, and then 504 g of acetonitrile was evaporated and desolvated at a temperature of 50° C., and the temperature was lowered to -5° C. for crystallization. The solid-liquid separation was carried out by suction filtration. The obtained solid product was dried at a temperature of 40° C. for 6 h to obtain 354 g of bromopyrrolecarbonitrile, and the yield was measured to be 94.3%. The acetonitrile in the obtained liquid phase was evaporated, and the evaporated acetonitrile was combined with the acetonitrile desolvated from the acetonitrile layer and dried over anhydrous sodium sulfate, and then returned to step (1).

[0048] Example 3 (1) In a 2 L reaction vessel, 185.6 g of p-chlorophenylglycine, 372 g of acetonitrile, 114.3 g of trifluoroacetic acid, and 5.6 g of triethylamine were mixed, and then 119 g of thionyl chloride was added dropwise while controlling the temperature at -10 ° C. The acylation reaction was then carried out at -10 ° C for 3 h. When the p-chlorophenylglycine was detected to be completely reacted, the reaction was purged with nitrogen; (2) Under nitrogen, 106 g of sodium carbonate was added to the mixture obtained in step (1) and mixed, and then 105 g of 2-chloroacrylonitrile was added dropwise at a temperature of 10° C., followed by a cyclization reaction at a temperature of 10° C. for 4 h. When it was detected that the product obtained in step (1) was completely reacted, the liquid phase was separated from the obtained mixture by filtration and transferred to a reaction vessel; (3) Under nitrogen, the liquid phase obtained in step (2), 172 g of hydrobromic acid with a concentration of 48 wt % and 172 g of hydrogen peroxide with a concentration of 30 wt % were mixed and bromination reaction was carried out at a temperature of 10° C. for 4 h. When it was detected that the product obtained in step (2) was completely reacted, the obtained mixture was allowed to stand for 25 min, and the aqueous layer was separated by stratification. The aqueous layer was extracted with 80 g of acetonitrile. The acetonitrile layer obtained by extraction and the acetonitrile layer obtained by stratification were mixed, and then 180 g of acetonitrile was evaporated and desolvated at a temperature of 90° C., and the temperature was lowered to 5° C. for crystallization. The solid-liquid separation was carried out by suction filtration. The obtained solid product was dried at a temperature of 50° C. for 2 h to obtain 338.7 g of bromopyrrolecarbonitrile, and the yield was measured to be 90.1%. The acetonitrile in the obtained liquid phase was evaporated, and the evaporated acetonitrile was combined with the acetonitrile desolvated from the acetonitrile layer and dried over anhydrous sodium sulfate, and then returned to step (1).

[0049] Example 4 (1) In a 2 L reaction vessel, 185.6 g of p-chlorophenylglycine, 1113 g of acetonitrile, 125.7 g of trifluoroacetic acid, and 0.2 g of triethylamine were mixed, and then 152.3 g of oxalyl chloride was added dropwise while controlling the temperature at -10 °C. The acylation reaction was then carried out at 20 °C for 1 h. When the p-chlorophenylglycine was detected to be completely reacted, the reaction was purged with nitrogen; (2) Under nitrogen, 126 g of sodium bicarbonate was added to the mixture obtained in step (1) and mixed, and then 87.5 g of 2-chloroacrylonitrile was added dropwise at a temperature of 40° C., followed by a cyclization reaction at 40° C. for 2 h. When it was detected that the product obtained in step (1) had completely reacted, the liquid phase was separated from the obtained mixture by filtration and transferred to a reaction vessel; (3) Under nitrogen, the liquid phase obtained in step (2), 168.6 g of hydrobromic acid with a concentration of 48 wt % and 241 g of hydrogen peroxide with a concentration of 30 wt % were mixed and bromination reaction was carried out at a temperature of 40° C. for 2 h. When it was detected that the product obtained in step (2) was completely reacted, the obtained mixture was allowed to stand for 40 min, and the aqueous layer was separated by stratification. The aqueous layer was extracted with 80 g of acetonitrile. The acetonitrile layer obtained by extraction and the acetonitrile layer obtained by stratification were mixed, and then 835 g of acetonitrile was evaporated and desolvated at a temperature of 40° C. The temperature was lowered to -15° C. for crystallization, and solid-liquid separation was carried out by suction filtration. The obtained solid product was dried at a temperature of 30° C. for 10 h to obtain 336.5 g of bromopyrrolecarbonitrile, with a measured yield of 89.5%. The acetonitrile in the obtained liquid phase was evaporated, and the evaporated acetonitrile was combined with the acetonitrile desolvated from the acetonitrile layer and dried over anhydrous sodium sulfate, and then returned to step (1).

[0050] Example 5 The method of Example 1 was followed, except that the commercially available acetonitrile was replaced with the acetonitrile recovered by drying in Example 1, to obtain 359 g of bromopyrrolecarbonitrile, with a yield of 95.5%.

[0051] Example 6 The method of Example 1 was followed, except that 92.4 g of sodium bicarbonate was replaced with 110.2 g of potassium bicarbonate to obtain 353.8 g of bromopyrrolecarbonitrile, with a measured yield of 94.1%.

[0052] Comparative Example 1 The method of Example 1 was followed, except that oxalyl chloride was replaced by phosphorus trichloride to obtain bromopyrrolecarbonitrile, and the yield was measured to be 86.3%.

[0053] Comparative Example 2 The method of Example 1 was followed, except that acetonitrile was replaced by DMF. The yield of the obtained bromopyrrole carbonitrile was 85.3%, and the DMF could not be recovered for reuse.

[0054] Comparative Example 3 The method of Example 1 was followed, except that sodium bicarbonate was replaced by triethylamine. The yield of the obtained bromopyrrolecarbonitrile was 86.1%.

[0055] By comparing Examples 1-6 with Comparative Examples 1-3, it can be seen that the examples using the preparation method of bromopyrrole carbonitrile of the present invention have a higher reaction yield, do not require frequent replacement of different solvents, and the solvent can be recycled and reused.

[0056] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as the contents disclosed by the present invention and fall within the scope of protection of the present invention.

Claims

1. A method for preparing bromopyrrole carbonitrile, characterized in that: The method comprises the following steps: (1) p-Chlorophenylglycine, acetonitrile, trifluoroacetic acid and a catalyst are mixed, followed by dropwise addition of acyl chloride and acylation reaction. After the reaction is complete, the mixture is purged with an inert gas; (2) mixing the mixture obtained in step (1) and an inorganic salt under the inert gas, then adding 2-chloroacrylonitrile dropwise and performing a cyclization reaction, and separating a liquid phase from the obtained mixture; (3) Under the inert gas, the liquid phase obtained in step (2), hydrobromic acid and hydrogen peroxide are mixed and subjected to bromination reaction, followed by extraction with acetonitrile to obtain an acetonitrile layer, followed by desolvation of the acetonitrile, and then cooling and crystallization to obtain bromopyrrole carbonitrile.

2. The method according to claim 1, characterized in that In step (1), the mass ratio of the p-chlorophenylglycine to the acetonitrile is 1:(2-6); Preferably, in step (1), the molar ratio of the p-chlorophenylglycine to the trifluoroacetic acid is 1:(1-1.1).

3. The method according to claim 1 or 2, characterized in that In step (1), the acyl chloride is thionyl chloride and / or oxalyl chloride; Preferably, the molar ratio of the p-chlorophenylglycine to the acyl chloride is 1:(1-1.2).

4. The method according to any one of claims 1 to 3, characterized in that In step (1), the temperature is controlled to be -10 to 20°C when the acid chloride is added dropwise; Preferably, in step (1), the conditions of the acylation reaction include: temperature of -10 to 20°C, and time of 1 to 3 hours.

5. The method according to any one of claims 1 to 4, characterized in that In step (1), the catalyst is an organic weak base, preferably triethylamine and / or DMF; Preferably, in step (1), the mass ratio of the catalyst to the p-chlorophenylglycine is 0.1%-3%.

6. The method according to any one of claims 1 to 5, characterized in that In step (2), the inorganic salt is an alkaline inorganic salt, preferably at least one of sodium bicarbonate, sodium carbonate and potassium bicarbonate; Preferably, the molar ratio of the inorganic salt to the p-chlorophenylglycine is 1:(1-1.5).

7. The method according to any one of claims 1 to 6, characterized in that In step (2), the molar ratio of the p-chlorophenylglycine to the 2-chloroacrylonitrile is 1:(1-1.2); Preferably, in step (2), the temperature is controlled to be 10-40°C when 2-chloroacrylonitrile is added dropwise; Preferably, in step (2), the conditions of the cyclization reaction include: temperature of 10-40° C. and time of 2-4 h.

8. The method according to any one of claims 1 to 7, characterized in that In step (3), the molar ratio of the p-chlorophenylglycine to the hydrobromic acid is 1:(1-1.1); Preferably, in step (3), the mass ratio of the hydrobromic acid to the hydrogen peroxide is (0.7-1):1; Preferably, in step (3), the conditions of the bromination reaction include: temperature of 10-40° C. and time of 2-4 h.

9. The method according to any one of claims 1 to 8, characterized in that In step (3), when the volume of acetonitrile removed by desolvation is 40%-70% of the volume when added, cooling crystallization is performed; Preferably, the temperature of the cooling crystallization is -15 to 5°C.

10. The method according to any one of claims 1 to 9, characterized in that The method further comprises: after the cooling crystallization, performing solid-liquid separation, distilling off the acetonitrile in the obtained liquid phase, and combining the distilled acetonitrile with the acetonitrile desolvated from the acetonitrile layer and then reusing the combined acetonitrile in step (1).

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