Process for the preparation of 2-nitro-4-(trifluoromethyl)benzonitrile

Abstract

The present application relates to the field of herbicides, in particular to a preparation method of 2-nitro-4-(trifluoromethyl)benzonitrile. The method comprises the following steps: 1) under the presence of a first solvent, a compound shown in formula I is subjected to ammoniation reaction with an ammoniation reagent under ammoniation reaction conditions to obtain a compound shown in formula II, wherein X represents halogen in formula I; 2) under the presence of a second solvent, the compound shown in formula II is subjected to diazotization reaction with a diazotization reagent under diazotization reaction conditions to obtain a diazotization reaction product; 3) under the presence of a base, the diazotization reaction product obtained in step 2) is subjected to cyanation reaction with cyanide under cyanation reaction conditions. The method has mild reaction conditions, does not need to be carried out under high temperature conditions, and does not need to use a catalyst, so that the production cost is greatly reduced, and meanwhile a higher product yield and purity can be obtained.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of herbicides, in particular to a preparation method of 2-nitro-4-(trifluoromethyl)benzonitrile. BACKGROUND

[0002] The benzoylisoxazole herbicides such as isoxaflutole, pyrasulfotole, etc. are a kind of broad-spectrum herbicides, which are a kind of hydroxyphenyl pyruvic acid ester double oxidation enzyme inhibitors, inhibit the synthesis of hydroxyphenyl pyruvic acid ester double oxidation enzyme, cause tyrosine accumulation, hinder the biosynthesis of plastoquinone and tocopherol, and further affect the biosynthesis of carotenoids.

[0003] 2-nitro-4-(trifluoromethyl)benzonitrile is one of the important intermediates for synthesizing isoxazole herbicides.

[0004] At present, the method for synthesizing 2-nitro-4-(trifluoromethyl)benzonitrile mainly uses 2-nitro-4-(trifluoromethyl)chlorobenzene as a raw material, and directly performs cyanation reaction with cyanide to obtain the product in one step. However, the above reaction needs to use a catalyst and is carried out at high temperature. Cyanide poisoning accidents are prone to occur in the high-temperature reaction process, which seriously endangers the life safety of production personnel, and tar is easily produced at high temperature, which makes the post-treatment difficult. In addition, due to the use of the catalyst, the preparation cost is high. SUMMARY

[0005] The purpose of the present application is to overcome the problems in the prior art that 2-nitro-4-(trifluoromethyl)benzonitrile is prone to cause cyanide poisoning accidents in the preparation process, and the post-treatment is difficult, and to provide a preparation method of 2-nitro-4-(trifluoromethyl)benzonitrile. The method has mild reaction conditions, does not need to be carried out at high temperature, and does not need to use a catalyst, which can ensure production safety, greatly reduce production cost, and obtain high yield and purity.

[0006] In order to achieve the above purpose, the present application provides a preparation method of 2-nitro-4-(trifluoromethyl)benzonitrile, which comprises the following steps:

[0007] 1) under the presence of a first solvent, performing an amination reaction on a compound shown in formula I with an amination reagent under amination reaction conditions to obtain a compound shown in formula II, wherein X in formula I represents halogen;

[0008] Formula I, Formula II

[0009] 2) under the presence of a second solvent, performing a diazotization reaction on the compound shown in formula II with a diazotization reagent under diazotization reaction conditions to obtain a diazotization reaction product;

[0010] 3) subjecting the diazotization reaction product obtained in step 2) to a cyanation reaction with a cyanide under cyanation reaction conditions in the presence of a base.

[0011] Preferably, the compound of formula I is prepared by the following method:

[0012] subjecting the halogenated p-trifluoromethylbenzene to a nitration reaction with a nitration agent under nitration reaction conditions in the presence of an acid.

[0013] Preferably, the acid is one or more of sulfuric acid, phosphoric acid and acetic acid, more preferably sulfuric acid.

[0014] Preferably, the halogenated p-trifluoromethylbenzene is one or more of p- fluorotri-fluoromethylbenzene, p-chlorotri-fluoromethylbenzene and p-bromotri- fluoromethylbenzene, more preferably p-chlorotri-fluoromethylbenzene.

[0015] Preferably, the nitration agent is one or more of nitric acid, sodium nitrate and potassium nitrate, more preferably nitric acid.

[0016] Preferably, the molar ratio of the halogenated p-trifluoromethylbenzene to the nitration agent is 1:1-1.5, more preferably 1:1-1.05.

[0017] Preferably, the molar ratio of the acid to the nitration agent is 1-5:1, more preferably 1-3:1.

[0018] Preferably, the nitration reaction conditions comprise a reaction temperature of 0-80°C, more preferably 10-50°C, further preferably 20-25°C; and a reaction time of 1-5h, more preferably 1-3h, further preferably 1-2h.

[0019] Preferably, in step 1), the first solvent is one or more of methanol, ethanol, n-propanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide, preferably methanol and / or ethanol.

[0020] Preferably, the aminating agent is ammonia gas and / or aqueous ammonia, more preferably aqueous ammonia.

[0021] Preferably, in step 1), the molar ratio of the compound of formula I to the aminating agent is 1:1-10, more preferably 1:1-5.

[0022] Preferably, the amount of the first solvent used is 100-400mL, more preferably 200-300mL, relative to 1 mol of the compound of formula I.

[0023] Preferably, the amination reaction conditions comprise: a reaction temperature of 0-100°C, more preferably 10-50°C, further preferably 20-30°C; a reaction time of 1-10h, more preferably 2-6h, further preferably 3-5h.

[0024] Preferably, in step 2), the second solvent is one or more of methanol, ethanol, acetic acid and sulfuric acid, more preferably acetic acid.

[0025] Preferably, the diazotization reagent is one or more of nitrosyl sulfuric acid, sodium nitrite, butyl nitrite and isoamyl nitrite; more preferably nitrosyl sulfuric acid and / or sodium nitrite; further preferably nitrosyl sulfuric acid.

[0026] Preferably, in step 2), the molar ratio of the compound of formula II to the diazotization reagent is 1:0.5-1.5; more preferably 1:1-1.1.

[0027] Preferably, the amount of the second solvent used is 100-500mL, more preferably 200-400mL, relative to 1 mol of the compound of formula II.

[0028] Preferably, the diazotization reaction conditions comprise: a reaction temperature of -10 to 50°C, more preferably 0-30°C, further preferably 10-15°C; a reaction time of 0.1-5h, more preferably 0.5-3h, further preferably 1-2h.

[0029] Preferably, in step 3), the base is one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and potassium bicarbonate, more preferably potassium carbonate and / or sodium carbonate.

[0030] Preferably, the base is used in the form of an aqueous solution of the base.

[0031] Preferably, the cyanide is one or more of sodium cyanide, potassium cyanide and cuprous cyanide; more preferably a mixture of sodium cyanide and cuprous cyanide; further preferably, the molar ratio of the sodium cyanide to the cuprous cyanide is 2-4:1.

[0032] Preferably, in step 3), the molar ratio of the compound of formula II to the cyanide is 1:1-5, more preferably 1:1-3.

[0033] Preferably, the amount of the base used is such that the pH value of the reaction system is 7-14, more preferably 7-8.5, further preferably 7-7.5.

[0034] Preferably, the cyanation reaction conditions comprise: a reaction temperature of 0-50°C, preferably 10-50°C, more preferably 30-40°C; a reaction time of 1-8h, preferably 1-4h, more preferably 1-2h.

[0035] By the technical scheme, 2-nitro-4-(trifluoromethyl)benzonitrile is prepared by using halogenated p-trifluoromethylbenzene as a starting reaction material, the reaction material is cheap and easy to obtain, and the reaction steps are simple, so that the production cost can be greatly reduced.

[0036] In addition, the reaction condition of the method is very mild, and high-temperature heating is not required, so that cyanide poisoning problem that may be generated in the preparation process is avoided, the life safety of the production personnel is ensured, and the possibility of production accidents is greatly reduced.

[0037] Secondly, when the preparation method is used for production, no tar and the like are generated in the production process, and the post-treatment operation is very simple.

[0038] On the other hand, the method does not need to use a catalyst, the production cost is significantly reduced, and the yield and purity of the prepared 2-nitro-4-(trifluoromethyl)benzonitrile are relatively high, and the method is very suitable for large-scale industrial production. DETAILED DESCRIPTION

[0039] The endpoints of the ranges and any values disclosed herein are not limited to the precise values stated. The endpoints of the ranges and any values are understood to be approximate values. The endpoints of the ranges and any values are understood to be approximate values. The approximate values include values approximating the stated endpoint. For ranges, the endpoints of the ranges are combined with the other endpoints to create new ranges that are not expressly disclosed, but are included in the disclosure. For example, a range from 1 to 10 should be read to include the value of 10. The upper and lower limits of these changes can be expressed or inferred.

[0040] The present application provides a preparation method of 2-nitro-4-(trifluoromethyl)benzonitrile, wherein the method comprises the following steps:

[0041] 1) under the presence of a first solvent, a compound shown in formula I is subjected to an ammoniation reaction with an ammoniation reagent under ammoniation reaction conditions to obtain a compound shown in formula II, wherein X in formula I represents halogen;

[0042] Formula I, Formula II

[0043] 2) under the presence of a second solvent, the compound shown in formula II is subjected to a diazotization reaction with a diazotization reagent under diazotization reaction conditions to obtain a diazotization reaction product;

[0044] 3) under the presence of a base, the diazotization reaction product obtained in step 2) is subjected to a cyanation reaction with cyanide under cyanation reaction conditions.

[0045] In the present application, the compound of formula I can be commercially available or prepared. In order to further reduce the production cost, the compound of formula I is preferably prepared by the following preparation method.

[0046] The preparation method of the compound of formula I comprises: in the presence of an acid, nitration reaction of halogenated p-trifluoromethylbenzene (wherein X represents halogen, which can be, for example, fluorine, chlorine, bromine and iodine) and a nitrating agent under nitration reaction conditions.

[0047] In the above method, the halogenated p-trifluoromethylbenzene can be a conventional choice in the art, which can be, for example, one or more of p-fluorotri-fluoromethylbenzene, p-chlorotri-fluoromethylbenzene and p-bromotri-fluoromethylbenzene. Here, in order to improve the yield in the subsequent preparation of 2-nitro-4-(trifluoromethyl)benzonitrile, preferably, the halogenated p-trifluoromethylbenzene is p-chlorotri-fluoromethylbenzene, i.e. X is preferably chlorine.

[0048] In the present application, the nitrating agent is not particularly limited as long as it can perform nitration reaction with the halogenated p-trifluoromethylbenzene to obtain the compound of formula I. The nitrating agent can be, for example, one or more of nitric acid, sodium nitrate and potassium nitrate. In order to improve the reaction rate and product yield, the nitrating agent is preferably nitric acid.

[0049] In addition, in the present application, the amount of the nitrating agent can be selected according to the amount of the halogenated p-trifluoromethylbenzene. For example, the molar ratio of the halogenated p-trifluoromethylbenzene to the nitrating agent can be 1:1-1.5, preferably 1:1-1.2, and more preferably 1:1-1.05. In this way, not only can the reaction rate of the nitration reaction be improved, but also the cost can be reduced and the product yield can be increased.

[0050] In the present application, the nitration reaction is preferably carried out in the presence of an acid, which not only provides a reaction environment for the nitration reaction, but also further promotes the reaction, improves the reaction rate and increases the yield of the obtained product.

[0051] Here, the acid is not particularly limited and can be a conventional choice in the art, which can be, for example, one or more of sulfuric acid, phosphoric acid and acetic acid, preferably sulfuric acid and acetic acid, and more preferably sulfuric acid. In this way, the reaction rate can be further improved.

[0052] In a preferred embodiment of the present application, the nitrating agent of the nitration reaction is nitric acid and the acid is sulfuric acid. At this time, the nitration reaction is preferably carried out by adding the raw material halogenated p-trifluoromethylbenzene in a mixed acid system of nitric acid and sulfuric acid.

[0053] ​Further, the acid is preferably used in the form of an aqueous solution, and preferably, in the aqueous solution of the acid, the content of the acid is 60-90% by weight, further preferably 60-70% by weight.

[0054] In addition, the amount of the acid can be selected according to the amount of the nitrating agent, for example, the molar ratio of the acid to the nitrating agent can be 1-5:1, preferably 1-3:1.

[0055] In the present application, the conditions of the nitration reaction are not particularly limited, and the conventional nitration reaction conditions in the art can be used. For example, the nitration reaction conditions can include: the reaction temperature is 0-80°C; the reaction time is 1-5h; preferably, the nitration reaction conditions include: the reaction temperature is 10-50°C; the reaction time is 1-3h; more preferably, the nitration reaction conditions include: the reaction temperature is 20-25°C; the reaction time is 1-2h. By carrying out the nitration reaction under the above conditions, not only can the nitration reaction be carried out at a higher rate, but also the yield of the compound represented by formula I prepared by the nitration reaction can be improved.

[0056] Hereinafter, the preparation method of 2-nitro-4-(trifluoromethyl)benzonitrile from the compound represented by formula I will be described in detail.

[0057] The inventors of the present application found that when the compound represented by formula I is directly prepared into 2-nitro-4-(trifluoromethyl)benzonitrile by using the conventional method, the reaction requires a high temperature (generally about 150-200°C), and therefore a large amount of cyanide, which is seriously toxic to human body, is generated during the reaction, seriously threatening the life and health of the operating personnel. Moreover, the above reaction needs to be carried out in the presence of a catalyst, thereby greatly increasing the production cost. From the aspects of operation safety and production economy, the existing one-step process for preparing 2-nitro-4-(trifluoromethyl)benzonitrile is not suitable for large-scale industrial production.

[0058] Based on this, the inventors of the present application found through a large amount of research that by first carrying out the amination reaction of the compound represented by formula I to obtain the compound represented by formula II, and then sequentially carrying out the diazotization reaction and cyanation reaction of the compound represented by formula II, the above reactions can be carried out under very mild reaction conditions, and no toxic cyanide substance is generated, thereby greatly improving the safety of production. Moreover, no catalyst is needed at all during the reaction process described in the present application, thereby greatly reducing the cost. In addition, the preparation process and the post-treatment process described in the present application are simple and easy to operate, and are very suitable for large-scale industrial production, thereby providing a new idea and preparation process for the preparation of 2-nitro-4-(trifluoromethyl)benzonitrile.

[0059] Hereinafter, the amination reaction of step 1) will be described in detail.

[0060] In step 1), the compound of formula I is subjected to an amination reaction with an amination reagent in the presence of a first solvent under amination reaction conditions to obtain a compound of formula II.

[0061] According to the present application, the first solvent is not particularly limited and can be any of various solvents conventionally used in the art for amination reactions. For example, the first solvent can be one or more of methanol, ethanol, n-propanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. In the present application, the first solvent is preferably methanol and / or ethanol, which can further facilitate the amination reaction and improve the yield of the amination reaction.

[0062] In addition, in the present application, the amount of the first solvent is not particularly limited and can be any amount that allows the amination reaction to proceed smoothly. For example, the amount of the first solvent can be 100-400 mL, preferably 200-300 mL, per 1 mol of the compound of formula I. This not only ensures that the amination reaction proceeds smoothly, but also reduces production costs while ensuring reaction rate and product yield.

[0063] According to the present application, the amination reagent can be any of various amination reagents used in the art for amination reactions. In the present application, the amination reagent is preferably ammonia gas and / or aqueous ammonia, and more preferably aqueous ammonia. The inventors of the present application have found that when aqueous ammonia is used for the amination reaction, the operation is more convenient compared to using ammonia gas for the amination reaction, and the yield of the amination reaction and the purity of the final product can be further improved.

[0064] In addition, in the present application, the amount of the amination reagent is not particularly limited and can be selected according to the amount of the compound of formula I. For example, the molar ratio of the compound of formula I to the amination reagent can be 1:1-10, preferably 1:1-5. This not only further ensures the rate of the amination reaction, but also avoids waste, making the reaction more complete and thereby further improving the yield of step 1).

[0065] According to the present application, in step 1), the conditions of the amination reaction are not particularly limited and can be any of conventional choices in the art. For example, the conditions of the amination reaction can include a reaction temperature of 0-100°C and a reaction time of 1-10 h. In addition, to further improve the rate of the amination reaction and improve the yield of the product, the amination reaction conditions preferably include a reaction temperature of 10-50°C and a reaction time of 2-6 h. More preferably, the amination reaction conditions include a reaction temperature of 20-30°C and a reaction time of 3-5 h.

[0066] In addition, in the present application, when the aminating agent in the amination reaction of step 1) is ammonia, in order to increase the solubility of ammonia in the reaction system, thereby further promoting the rapid progress of the reaction, preferably, the amination reaction conditions further comprise: the reaction pressure is 0.1-2 MPa, more preferably 0.5-1 MPa.

[0067] In a preferred embodiment of the present application, in step 1), ethanol is used as the first solvent, and ammonia is used as the aminating agent to react with the compound of formula I, and the molar ratio of the compound of formula I to ammonia is 1:3-5, and the amination reaction conditions comprise: the reaction temperature is 25-30°C; the reaction time is 3-5 h, thereby ensuring that the yield of the compound of formula II is more than 99%.

[0068] In addition, according to the present application, after the amination reaction of step 1), the compound of formula II obtained by the reaction can be separated by solid-liquid separation, and the solid phase obtained by solid-liquid separation can be further treated by drying or the like. The solid-liquid separation and drying or the like can be carried out by conventional methods in the art, which will not be described here.

[0069] Next, the diazotization reaction of step 2) will be described in detail.

[0070] In step 2), the compound of formula II is subjected to a diazotization reaction with a diazotization agent in the presence of a second solvent under diazotization reaction conditions to obtain a diazotization reaction product.

[0071] In the present application, the second solvent is not particularly limited and can be various solvents conventionally used for diazotization reactions in the art. For example, the second solvent can be one or more of methanol, ethanol, acetic acid, and sulfuric acid, and is preferably acetic acid.

[0072] In addition, the amount of the second solvent is not particularly limited and can be a conventional selection in the art. The amount of the second solvent can be selected according to the amount of the compound of formula II. For example, the amount of the second solvent can be 100-500 mL, preferably 200-400 mL, per 1 mol of the compound of formula II. This not only ensures that the diazotization reaction proceeds more smoothly, but also further improves the reaction rate and product yield.

[0073] In the present application, the diazotization agent can be various agents conventionally used in the art that can be used for diazotization reaction with the compound of formula II, and is not particularly limited, for example, it can be one or more of nitrosyl sulfuric acid, sodium nitrite, butyl nitrite, and isoamyl nitrite, wherein, preferably, it is nitrosyl sulfuric acid and / or sodium nitrite, more preferably, it is nitrosyl sulfuric acid.

[0074] The inventors of the present application found in the research process that when nitroso sulfuric acid is used for the diazotization reaction in step 2), no additional acid needs to be added during the reaction, the operation is more convenient, and the yield of the diazotization reaction product can be further improved, thereby improving the yield of 2-nitro-4-(trifluoromethyl)benzonitrile.

[0075] In addition, in the present application, the amount of the diazotization reagent can be adjusted according to the amount of the compound of formula II, for example, the molar ratio of the compound of formula II to the diazotization reagent can be 1:0.5-1.5, preferably 1:1-1.5, and more preferably 1:1-1.1. In this way, the sufficient reaction of the compound of formula II can be ensured while further reducing the production cost, and the yield of the product can be improved.

[0076] In the present application, the conditions of the diazotization reaction are not particularly limited, as long as the compound of formula II can react with the diazotization reagent to form a diazonium salt. For example, the diazotization reaction conditions can include a reaction temperature of -10 to 50°C and a reaction time of 0.1-5h; preferably, the diazotization reaction conditions can include a reaction temperature of 0-30°C and a reaction time of 0.5-3h; more preferably, the diazotization reaction conditions can include a reaction temperature of 10-15°C and a reaction time of 1-2h.

[0077] Through the diazotization reaction of step 2), the compound of formula II can be converted into a diazonium salt of the compound of formula II, which has very good reactivity, so that it can react with cyanide at a lower temperature without the use of a catalyst to prepare 2-nitro-4-(trifluoromethyl)benzonitrile. In this way, cyanide poisoning during high-temperature reaction can be avoided, and the production cost can be further reduced while ensuring high yield and high purity.

[0078] In addition, after the reaction of step 2) is completed, the diazonium salt of the compound of formula II produced by the diazotization reaction can be directly used for the subsequent reaction of step 3) without separation, and the process is very simple.

[0079] The cyanation reaction of step 3) is described in detail below.

[0080] In step 3), the diazotization reaction product obtained in step 2) is reacted with cyanide in the presence of a base under cyanation reaction conditions.

[0081] According to the present application, in order to ensure the safety of the reaction and the effectiveness of the cyanation reagent, the cyanation reaction is preferably carried out in the presence of a base.

[0082] The kind of the base in step 3) is not particularly limited, and for example, various alkali metal hydroxides, carbonates, bicarbonates and the like commonly used in the art can be used. Specifically, the base can be one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and potassium bicarbonate, and preferably, potassium carbonate or sodium carbonate.

[0083] In addition, in the present application, the base can be added directly in solid form or can be prepared into a solution for use. In order to increase the convenience of operation during the cyanation reaction process and improve the safety and efficiency of the reaction, preferably, the base is used in the form of an aqueous solution of the base.

[0084] In addition, in the present application, the amount of the base is not particularly limited, and the pH of the reaction system in step 3) should be 7-14. In order to further improve the efficiency of the reaction, the pH is preferably 7-8.5, more preferably 7-7.5, and particularly preferably 7-7.2. By adjusting the pH of the reaction system in step 3) to the above range using the base, the yield of the reaction can be maximized while ensuring the safety of production.

[0085] According to the present application, the kind of the cyanide is not particularly limited, and can be one or more of sodium cyanide, potassium cyanide and cuprous cyanide commonly used in the art.

[0086] In addition, in step 3), the amount of the cyanide can be determined according to the amount of the compound of formula II, and for example, the molar ratio of the compound of formula II to the cyanide can be 1:1-5, preferably 1:1-3, and more preferably 1:1-2. In this way, the reaction in step 3) can be made more complete, and the reaction rate and the yield of the product can be ensured.

[0087] The inventors of the present application have found that when a mixture of sodium cyanide and cuprous cyanide is used to perform the cyanation reaction in step 3), the yield of the product can be significantly improved. Therefore, in the present application, it is particularly preferred that the cyanide is a mixture of sodium cyanide and cuprous cyanide.

[0088] In addition, the inventors of the present application have also found that when the cyanide is a mixture of sodium cyanide and cuprous cyanide, the molar ratio of the two will have a significant impact on the yield of the product, and when the molar ratio of the sodium cyanide to the cuprous cyanide is 2-4:1, the yield of the product obtained by the cyanation reaction is significantly improved. Therefore, in the present application, it is preferred that the molar ratio of the sodium cyanide to the cuprous cyanide is 2-4:1.

[0089] In addition, in a particularly preferred embodiment of the present application, a mixture of sodium cyanide and cuprous cyanide is used as the cyanide in step 3) for the cyanation reaction, and the molar ratio of the sodium cyanide to the cuprous cyanide is 3:1. In this case, the cyanation reaction in step 3) can achieve a very high yield.

[0090] In step 3) of the present application, the order of adding the diazotization reaction product obtained in step 2), the cyanide and the base is not particularly limited. For example, the cyanide can be first added to the diazotization reaction product, and then the base is used to adjust the pH value of the mixture; or the cyanide can be first mixed with water, and then the diazotization reaction product obtained in step 2) and the base are added.

[0091] In a preferred embodiment of the present application, the cyanide is first added to a reaction vessel, and then water is added to mix the cyanide thoroughly, and then the diazotization reaction product obtained in step 2) and the base are added dropwise. In this way, the reaction can be made more complete, and the reaction efficiency and the yield of the product can be improved.

[0092] According to the present application, since the diazotization reaction product obtained in step 2) is highly active, and the cyanation reaction is carried out with the cyanide, the conditions for the cyanation reaction in step 3) are very mild, and the reaction can be carried out smoothly without high-temperature heating and without using any catalyst. In this way, cyanide poisoning that can occur during the cyanation reaction is avoided, and the use of a catalyst is avoided, so that the production cost can be greatly reduced while ensuring production safety.

[0093] According to the present application, the conditions for the cyanation reaction in step 3) can include: the reaction temperature is 0-50°C, preferably 10-50°C, and more preferably 30-40°C; and the reaction time is 1-8h, preferably 1-4h, and more preferably 1-2h. Under the above reaction conditions, the cyanation reaction can be realized without high-temperature heating and without using a catalyst, and in addition, the yield of 2-nitro-4-(trifluoromethyl)benzonitrile prepared can be ensured to be above 90%.

[0094] In a particularly preferred embodiment of the present application, in step 1), ammonia is used for the amination reaction, and in step 3), a mixture of sodium cyanide and cuprous cyanide is used for the cyanation reaction, and the molar ratio of the sodium cyanide to the cuprous cyanide is 2-4:1, for example, it can be 2:1, 3:1, 4:1, etc. Through the selection and amount ratio limitation of the above raw materials, the yield can be further significantly improved, and it is very suitable for large-scale industrial production.

[0095] The present application will be described in detail below through examples, but the present application is not limited to the following examples.

[0096] In the following examples, the raw materials used are all conventional commercially available products unless otherwise specified.

[0097] Example 1

[0098] 1) In a 500ml four-necked flask equipped with a thermometer, a condenser and a mechanical stirrer, 0.9mol of sulfuric acid (using 65wt% aqueous sulfuric acid solution) was added, followed by dropwise addition of 0.315mol of nitric acid (using 65wt% aqueous nitric acid solution), then 0.3mol of p-chlorobenzotrifluoride was added dropwise at 25°C, and the reaction was carried out for 1h. After the reaction was completed, the organic phase was separated and dried to obtain 4-chloro-3-nitrobenzotrifluoride (determined by NMR and mass spectrometry to be 4-chloro-3-nitrobenzotrifluoride). The yield of this step was 99%.

[0099] 2) In a 500ml reaction flask equipped with a thermometer, a condenser and a mechanical stirrer, 0.3mol of 4-chloro-3-nitrobenzotrifluoride prepared according to the method described in step 1) and 67ml of ethanol were added, and after warming to 25°C, 1.5mol of ammonia water was added dropwise, and after reaction at 30°C for 4h, the reaction system was cooled to 10°C, then the reaction product was filtered, and the filter cake was dried to obtain 4-amino-3-nitrobenzotrifluoride (determined by NMR and mass spectrometry to be 4-amino-3-nitrobenzotrifluoride). The yield of this step was 99%.

[0100] 3) In a 500ml four-necked flask equipped with a thermometer, a condenser and a mechanical stirrer, 0.315mol of nitrosyl sulfuric acid was added, and after cooling to 15°C, a mixture of 0.3mol of 4-amino-3-nitrobenzotrifluoride prepared according to the method described in step 2) and 120ml of acetic acid was added dropwise, and after the addition was completed, the reaction was carried out at 10°C for 1.5h to obtain a diazo reaction product.

[0101] 4) In a 500ml four-necked flask equipped with a thermometer, a condenser and a mechanical stirrer, 0.3mol of sodium cyanide, 0.1mol of cuprous cyanide and 85ml of water were added, and after warming to 35°C, the diazo reaction product obtained in step 3) was added, and a saturated aqueous solution of sodium carbonate was added dropwise to adjust the pH of the system to 7, and then the reaction was carried out at 35°C for 1h, and then cooled to 20°C, and a light yellow solid was obtained by filtration, which was determined by NMR and mass spectrometry to be 2-nitro-4-(trifluoromethyl)benzonitrile.

[0102] The yield of steps 3) and 4) was 96%, and the purity of the obtained 2-nitro-4-(trifluoromethyl)benzonitrile was 98% (determined by HPLC).

[0103] Example 2

[0104] 1) In a 500ml four-necked flask equipped with a thermometer, a condenser and a mechanical stirrer, 0.6mol of sulfuric acid (65% by weight aqueous solution of sulfuric acid) was added, followed by the dropwise addition of 0.315mol of nitric acid (65% by weight aqueous solution of nitric acid), then 0.3mol of p-chlorobenzotrifluoride was added dropwise at 20°C and the reaction was allowed to proceed for 1.5h. The reaction was then separated and the organic phase was dried to obtain 4-chloro-3-nitrobenzotrifluoride (determined by NMR and mass spectrometry to be 4-chloro-3-nitrobenzotrifluoride). The yield of this step was 98%.

[0105] 2) In a 500ml reaction flask equipped with a thermometer, a condenser and a mechanical stirrer, 0.3mol of 4-chloro-3-nitrobenzotrifluoride prepared according to the method described in step 1) and 60ml of ethanol were added. After warming to 20°C, 0.9mol of aqueous ammonia was added dropwise and the reaction was allowed to proceed for 5h at 20°C. The reaction was then cooled to 10°C and the reaction product was filtered and dried to obtain 4-amino-3-nitrobenzotrifluoride (determined by NMR and mass spectrometry to be 4-amino-3-nitrobenzotrifluoride). The yield of this step was 97%.

[0106] 3) In a 500ml four-necked flask equipped with a thermometer, a condenser and a mechanical stirrer, 0.9mol of sulfuric acid (65% by weight aqueous solution of sulfuric acid) was added, followed by the dropwise addition of 0.3mol of the reaction product prepared according to the method described in step 2). Then 0.33mol of sodium nitrite (30% by weight aqueous solution of sodium nitrite) was added dropwise at 5°C and the reaction was allowed to proceed for 2h to obtain a diazonium reaction product.

[0107] 4) In a 500ml four-necked flask equipped with a thermometer, a condenser and a mechanical stirrer, 0.32mol of sodium cyanide and 0.08mol of cuprous cyanide were added, followed by the addition of 85ml of water. After warming to 30°C, the diazonium reaction product obtained in step 3) was added, and a saturated aqueous solution of sodium carbonate was added dropwise to adjust the pH of the system to 7.5. The reaction was then allowed to proceed for 1h at 30°C, cooled to 20°C and filtered to obtain a light yellow solid, which was determined by NMR and mass spectrometry to be 2-nitro-4-(trifluoromethyl)benzonitrile.

[0108] The yield of steps 3) and 4) was 94% and the purity of the obtained 2-nitro-4-(trifluoromethyl)benzonitrile was 99% (determined by HPLC).

[0109] Example 3

[0110] 1) In a 500ml four-necked flask equipped with a thermometer, a condenser and a mechanical stirrer, 0.9mol of sulfuric acid (65% by weight aqueous solution of sulfuric acid) was added, followed by dropwise addition of 0.315mol of nitric acid (65% by weight aqueous solution of nitric acid), then 0.3mol of p-bromobenzotrifluoride was added dropwise at 25°C, and the reaction was allowed to proceed for 2h. After the reaction was completed, the organic phase was separated and dried to obtain 4-bromo-3-nitrobenzotrifluoride (determined by NMR and mass spectrometry to be 4-bromo-3-nitrobenzotrifluoride). The yield of this step was 98%.

[0111] 2) In a 500ml reaction flask equipped with a thermometer, a condenser and a mechanical stirrer, 0.3mol of 4-bromo-3-nitrobenzotrifluoride prepared according to the method described in step 1) and 90ml of ethanol were added, and after warming to 25°C, 1.2mol of aqueous ammonia was added dropwise, and after the reaction was allowed to proceed at 25°C for 3h, the reaction system was cooled to 10°C, then the reaction product was filtered, and the filter cake was dried to obtain 4-amino-3-nitrobenzotrifluoride (determined by NMR and mass spectrometry to be 4-amino-3-nitrobenzotrifluoride). The yield of this step was 96%.

[0112] 3) In a 500ml four-necked flask equipped with a thermometer, a condenser and a mechanical stirrer, 0.9mol of sulfuric acid (65% by weight aqueous solution of sulfuric acid) was added, followed by dropwise addition of 0.3mol of the reaction product prepared according to the method described in step 2), then 0.3mol of sodium nitrite (30% by weight aqueous solution of sodium nitrite) was added dropwise at 15°C, and the reaction was allowed to proceed for 2h to obtain a diazo reaction product.

[0113] 4) In a 500ml four-necked flask equipped with a thermometer, a condenser and a mechanical stirrer, 0.28mol of sodium cyanide and 0.12mol of cuprous cyanide were added, 85ml of water was added, and after warming to 40°C, the diazo reaction product obtained in step 3) was added, and a saturated aqueous solution of sodium carbonate was added dropwise to adjust the pH of the system to 7, then the reaction was allowed to proceed at 40°C for 1h, and after cooling to 20°C, a light yellow solid was obtained by filtration. It was determined by NMR and mass spectrometry to be 2-nitro-4-(trifluoromethyl)benzonitrile. The yield of steps 3) and 4) was 94%, and the purity of the obtained 2-nitro-4-(trifluoromethyl)benzonitrile was 98% (determined by HPLC).

[0114] Example 4

[0115] The method described in Example 1 was followed, except that in step 2),

[0116] In a 500ml autoclave, 0.3mol of 4-chloro-3-nitro-trifluoromethylbenzene and 67ml of ethanol were put in, and after the temperature was raised to 70°C, 1.5mol of ammonia was introduced, and the pressure was maintained at 0.8MPa, and after the reaction for 4h, the reaction system was cooled to 10°C, then the reaction product was filtered, and the filter cake was dried to obtain 4-amino-3-nitro-trifluoromethylbenzene (determined by NMR and mass spectrometry to be 4-amino-3-nitro-trifluoromethylbenzene), and the yield of this step was 98.6%.

[0117] The purity of the obtained 2-nitro-4-(trifluoromethyl)benzonitrile was 95% (determined by HPLC).

[0118] Example 5

[0119] According to the method of Example 1, except that in step 4),

[0120] 0.2mol of sodium cyanide and 0.2mol of cuprous cyanide were added instead of 0.3mol of sodium cyanide and 0.1mol of cuprous cyanide.

[0121] A light yellow solid was obtained by filtration, which was determined by NMR and mass spectrometry to be 2-nitro-4-(trifluoromethyl)benzonitrile.

[0122] The yield of steps 3) and 4) was 71%, and the purity of the obtained 2-nitro-4-(trifluoromethyl)benzonitrile was 94% (determined by HPLC).

[0123] Example 6

[0124] According to the method of Example 1, except that in step 4),

[0125] 0.4mol of cuprous cyanide was added instead of 0.3mol of sodium cyanide and 0.1mol of cuprous cyanide.

[0126] A light yellow solid was obtained by filtration, which was determined by NMR and mass spectrometry to be 2-nitro-4-(trifluoromethyl)benzonitrile.

[0127] The yield of steps 3) and 4) was 66%, and the purity of the obtained 2-nitro-4-(trifluoromethyl)benzonitrile was 92% (determined by HPLC).

[0128] Example 7

[0129] According to the method of Example 1, except that in step 4),

[0130] 0.4mol of sodium cyanide was added instead of 0.3mol of sodium cyanide and 0.1mol of cuprous cyanide.

[0131] The filtrate was a light yellow solid, which was determined to be 2-nitro-4- (trifluoromethyl)benzonitrile by NMR and mass spectrometry.

[0132] The yield of the two steps of step 3) and step 4) was 64%, and the purity of the obtained 2-nitro-4- (trifluoromethyl)benzonitrile was 91% (determined by HPLC).

[0133] Comparative Example 1

[0134] In a 500 mL reaction flask equipped with a thermometer and a dehydration device, 90 g of 3-nitro-4-chlorobenzotrifluoride (0.4 mol), 100 g of N-methylpyrrolidone, 100 g of toluene, 52.1 g of lithium bromide (0.6 mol), and 1.8 g of tetraphenylphosphonium bromide were added. After dehydration by heating to reflux until no water beads flowed out (about 1 h), 40.5 g of cuprous cyanide (0.45 mol) was added. The toluene was distilled off at normal pressure until the liquid temperature reached 160°C, and the temperature was controlled at 160°C for 3 h of reaction.

[0135] After the reaction was completed, the temperature was lowered to room temperature (0-40°C), 100 ml of concentrated hydrochloric acid and 100 mL of water were added, and after stirring, 150 mL of dichloromethane was added for extraction once, and the upper layer was added with 100 mL of dichloromethane for extraction once. The dichloromethane layers were combined, washed with hydrochloric acid and water once, and then separated. The organic layer was first recovered at normal pressure, and then the product was distilled off under reduced pressure. The purity was 96% (HPLC), and the yield was 90%.

[0136] The above describes the preferred embodiments of the present application, but the present application is not limited thereto. Within the technical concept of the present application, various simple modifications can be made to the technical solutions of the present application, including the combination of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as disclosed by the present application, and fall within the protection scope of the present application.

Claims

1. A process for the preparation of 2-nitro-4-(trifluoromethyl)benzonitrile, characterized in that, The method comprises the following steps: 1) under the presence of a first solvent, subjecting a compound shown in formula I to an ammoniation reaction with an ammoniation reagent under ammoniation reaction conditions to obtain a compound shown in formula II, wherein X represents halogen, the ammoniation reaction conditions comprise: a reaction temperature of 10-50°C; and a reaction time of 2-6h; Formula I, Formula II 2) under the presence of a second solvent, subjecting the compound shown in formula II to a diazotization reaction with a diazotization reagent under diazotization reaction conditions to obtain a diazotization reaction product, the diazotization reagent is nitrosyl sulfuric acid, and the diazotization reaction conditions comprise: a reaction temperature of 0-30°C; and a reaction time of 0.5-3h; 3) under the presence of a base, subjecting the diazotization reaction product obtained in step 2) to a cyanation reaction with a cyanide under cyanation reaction conditions, the amount of the base is such that the pH value of the reaction system is 7-14, the cyanation reaction conditions comprise: a reaction temperature of 10-50°C; and a reaction time of 1-4h, the cyanide is a mixture of sodium cyanide and cuprous cyanide, the molar ratio of the sodium cyanide to the cuprous cyanide is 2-4:1, and the molar ratio of the compound shown in formula II to the cyanide is 1:1-3.

2. The method of claim 1, wherein, The compound shown in formula I is prepared by the following method: under the presence of an acid, subjecting a halogenated p-trifluoromethylbenzene to a nitration reaction with a nitrating agent under nitration reaction conditions.

3. The method of claim 1, wherein, In step 1), the first solvent is one or more of methanol, ethanol, n-propanol, isopropanol, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; The ammoniation reagent is ammonia gas and / or ammonia water.

4. The method of claim 3, wherein, In step 1), the first solvent is methanol and / or ethanol. The ammoniation reagent is ammonia water.

5. The method of any of claims 1-4, wherein, In step 1), the molar ratio of the compound shown in formula I to the ammoniation reagent is 1:1-10. The amount of the first solvent is 100-400 mL relative to 1 mol of the compound shown in formula I.

6. The method of claim 5, wherein, In step 1), the molar ratio of the compound shown in formula I to the ammoniation reagent is 1:1-5. The amount of the first solvent is 200-300 mL relative to 1 mol of the compound shown in formula I.

7. The method of any one of claims 1-4, wherein, The ammoniation reaction conditions comprise: a reaction temperature of 20-30°C; and a reaction time of 3-5h.

8. The method of any one of claims 1-4, wherein, In step 2), the second solvent is one or more of methanol, ethanol, acetic acid and sulfuric acid.

9. The method of claim 8, wherein, The second solvent is acetic acid.

10. The method of any one of claims 1-4, wherein, In step 2), the molar ratio of the compound shown in formula II to the diazotization reagent is 1:0.5-1.

5. The amount of the second solvent is 100-500 mL relative to 1 mol of the compound shown in formula II.

11. The method of claim 10, wherein, In step 2), the molar ratio of the compound shown in formula II to the diazotization reagent is 1:1-1.

1. The amount of the second solvent is 200-400 mL relative to 1 mol of the compound shown in formula II.

12. The method of any one of claims 1-4, wherein, The diazotization reaction conditions comprise: a reaction temperature of 10-15°C; and a reaction time of 1-2h.

13. The method of any one of claims 1-4, wherein, In step 3), the base is one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and potassium bicarbonate; The base is used in the form of an aqueous solution of the base.

14. The method of claim 13, wherein, In step 3), the base is potassium carbonate and / or sodium carbonate.

15. The method of claim 1, wherein, The amount of the base in step 3) is such that the pH value of the reaction system is 7-8.

5.

16. The method of claim 15, wherein, The amount of the base in step 3) is such that the pH value of the reaction system is 7-7.

5.

17. The method of any one of claims 1-4, wherein, The cyanation reaction conditions include: the reaction temperature is 30-40℃; and the reaction time is 1-2h.

18. The method of claim 2, wherein, The acid is one or more of sulfuric acid, phosphoric acid and acetic acid; The halogenated p-trifluoromethylbenzene is one or more of p-fluorotri-fluoromethylbenzene, p-chlorotri-fluoromethylbenzene and p-bromotri-fluoromethylbenzene; The nitration agent is one or more of nitric acid, sodium nitrate and potassium nitrate.

19. The method of claim 18, wherein, The acid is sulfuric acid; The halogenated p-trifluoromethylbenzene is p-chlorotri-fluoromethylbenzene; The nitration agent is nitric acid.

20. The method of any one of claims 2, 18, and 19, wherein, The molar ratio of the halogenated p-trifluoromethylbenzene to the nitration agent is 1:1-1.5; The molar ratio of the acid to the nitration agent is 1-5:1; The nitration reaction conditions include: the reaction temperature is 0-80℃; and the reaction time is 1-5h.

21. The method of claim 20, wherein, The molar ratio of the halogenated p-trifluoromethylbenzene to the nitration agent is 1:1-1.05; The molar ratio of the acid to the nitration agent is 1-3:1; The nitration reaction conditions include: the reaction temperature is 20-25℃; and the reaction time is 1-2h.

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