2,3-Difluoro-6-(trifluoromethyl)-benzonitrile compound and preparation method thereof

Abstract

The invention discloses a kind of 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound and preparation method thereof. The preparation method includes step S1, and the raw material including 1,2,3-trifluoro-6-nitrobenzene and cyaniding agent is subjected to cyanolysis reaction to obtain 2,3-difluoro-6-nitro-benzonitrile;Step S2, 2,3-difluoro-6-nitro-benzonitrile is subjected to hydrogenation reduction reaction to obtain 2,3-difluoro-6-amino-benzonitrile;Step S3, 2,3-difluoro-6-amino-benzonitrile and diazotizing agent are subjected to diazotization reaction to obtain diazonium salt;And step S4, diazonium salt and trifluoromethylating agent are subjected to trifluoromethylation reaction to obtain 2,3-difluoro-6-(trifluoromethyl)-benzonitrile. The above preparation method uses cheap 1,2,3-trifluoro-6-nitrobenzene as raw material, and obtains 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound of high yield simply, quickly and at low cost.

Description

Technical Field

[0001] The present invention relates to the technical field of synthesis of 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compounds, and in particular to a 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound and a preparation method thereof. Background Art

[0002] As pesticide fungicides, N'-(cyclopropylmethoxy)benzamide oxime compounds have a unique mechanism of action, are safe and efficient, low in toxicity, and easily degradable. They have a high targeting effect on pathogens. They have a novel structure, a broad spectrum, and high efficiency. Their mode of action is different from that of existing fungicides, and they have become a new hotspot in fungicide research. At present, with the large-scale application of chemical agents, environmental pollution is increasing day by day, and the emergence of resistance of pathogenic microorganisms is inevitable. At the same time, food safety issues are receiving increasing attention. Pesticide reduction and production of safe and environmentally friendly antimicrobial agents are conducive to sustainable development.

[0003] 2,3-Difluoro-6-(trifluoromethyl)-benzonitrile is an important intermediate of N'-(cyclopropylmethoxy)benzamide oxime pesticides. The existing synthesis method uses butyl lithium (the price of butyl lithium has been increasing in recent years) and requires high temperature fluorination. In addition, the multiple reaction steps lead to high costs and high equipment requirements, which is not conducive to industrial production. Therefore, it is necessary to develop a new route for synthesizing 2,3-difluoro-6-(trifluoromethyl)-benzonitrile to reduce costs and reduce the three wastes.

[0004] According to the available information, the synthesis of 2,3-difluoro-6-(trifluoromethyl)-benzonitrile basically uses 3,4-difluoro-trifluoromethylbenzene, which is fluorinated and lithiated to prepare aldehyde, which is then reacted with hydroxylamine hydrochloride and finally dehydrated. The price of butyl lithium has been increasing in recent years, and high-temperature fluorination is required, resulting in high costs, which is not conducive to industrial implementation.

[0005] Summary of the invention

[0006] The main purpose of the present invention is to provide a 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound and a preparation method thereof, so as to solve the problem of high cost in the preparation method of 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound in the prior art.

[0007] In order to achieve the above-mentioned purpose, according to one aspect of the present invention, a method for preparing 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is provided, and the method comprises: step S1, subjecting a raw material comprising 1,2,3-trifluoro-6-nitrobenzene and a cyaniding agent to a cyanolysis reaction to obtain 2,3-difluoro-6-nitro-benzonitrile; step S2, subjecting 2,3-difluoro-6-nitro-benzonitrile to a hydrogenation reduction reaction to obtain 2,3-difluoro-6-amino-benzonitrile; step S3, subjecting 2,3-difluoro-6-amino-benzonitrile to a diazotization reaction with a diazotization agent to obtain a diazonium salt; and step S4, subjecting the diazonium salt to a trifluoromethylation reaction with a trifluoromethylating agent to obtain 2,3-difluoro-6-(trifluoromethyl)-benzonitrile.

[0008] Furthermore, in the above step S1, the cyaniding agent is sodium cyanide and / or potassium cyanide, and preferably the molar ratio of the cyaniding agent to 1,2,3-trifluoro-6-nitrobenzene is 1.1 to 1.5:1.

[0009] Furthermore, in the above step S1, the raw material also includes a first catalyst, and preferably the molar number of the first catalyst is 5-10% of the molar number of 1,2,3-trifluoro-6-nitrobenzene, and preferably the first catalyst is cuprous iodide.

[0010] Furthermore, in the above step S1, the raw material also includes a phase transfer catalyst, and the molar number of the phase transfer catalyst is preferably 10 to 30% of the molar number of 1,2,3-trifluoro-6-nitrobenzene, and the molar ratio of the first catalyst to the phase transfer catalyst is preferably 0.16 to 0.5:1, and the phase transfer catalyst is preferably tetrabutylammonium bromide and / or tetrabutylammonium chloride.

[0011] Furthermore, in the above step S1, the cyanolysis reaction is carried out in a solvent, and the solvent is preferably selected from any one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-pyrrolidone. The cyanolysis reaction temperature is preferably 20 to 50° C., and the cyanolysis reaction time is preferably 12 to 24 hours.

[0012] Furthermore, in the above step S2, the hydrogenation reduction reaction is carried out under the action of a second catalyst, and preferably the molar number of the second catalyst is 0.001 to 0.005 times the mass of 2,3-difluoro-6-nitro-benzonitrile, and preferably the second catalyst is selected from any one or more of 3% palladium carbon, 1% palladium carbon, and 5% palladium carbon.

[0013] Furthermore, in the above step S2, the hydrogen partial pressure of the hydrogenation reduction reaction is 0.1 to 0.5 MPa, the temperature of the hydrogenation reduction reaction is preferably 20 to 25° C., and the time of the hydrogenation reduction reaction is preferably 8 to 24 hours.

[0014] Furthermore, in the above step S4, the diazotization reagent is selected from any one or more of sodium nitrite, tert-butyl nitroso ester, and tert-amyl nitroso ester. Preferably, the diazotization reagent is 1.1 to 1.3 times the molar number of 2,3-difluoro-6-amino-benzonitrile. Preferably, the pH value of the diazotization reaction is 1 to 3, and preferably the temperature of the diazotization reaction is 0 to 10°C.

[0015] Furthermore, in the above step S4, the trifluoromethylation reagent is sodium trifluoromethylsulfinate and / or potassium trifluoromethylsulfinate, and the trifluoromethylation reagent is preferably 3 to 4 times the molar number of the diazonium salt; preferably, an oxidant is added in the trifluoromethylation reaction, and the amount of the oxidant added is preferably 2 to 3 times the molar number of the diazonium salt, and the oxidant is preferably tert-butyl peroxide; preferably, a third catalyst is added to catalyze the trifluoromethylation reaction, and the amount of the third catalyst added is preferably 2 to 3 times the molar number of the diazonium salt, and the third catalyst is preferably cuprous chloride and / or cuprous bromide; preferably, the pH value of the trifluoromethylation reaction is 1 to 3, and the temperature of the trifluoromethylation reaction is preferably 0 to 10°C.

[0016] According to another aspect of the present invention, a 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound is provided. The 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound is prepared by the above preparation method.

[0017] The technical scheme of the present invention is applied. The present invention uses 1,2,3-trifluoro-6-nitrobenzene as a raw material, first reacts with cuprous cyanide or sodium cyanide to obtain 2,3-difluoro-6-nitro-benzonitrile, then hydrogenates to obtain 2,3-difluoro-6-amino-benzonitrile, and then completes a diazotization reaction and reacts with trifluoromethylation to prepare 2,3-difluoro-6-(trifluoromethyl)-benzonitrile. The above preparation method of the present application uses cheap 1,2,3-trifluoro-6-nitrobenzene as a raw material, and through the above reaction steps under mild reaction conditions, a high-yield 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound is obtained simply, quickly, and at low cost, and is more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The drawings constituting a part of the present application are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0019] Figure 1 The mass spectrum of 2,3-difluoro-6-(trifluoromethyl)-benzonitrile provided according to Example 1 of the present invention is shown. DETAILED DESCRIPTION

[0020] It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present application can be combined with each other. The present invention will be described in detail below with reference to the accompanying drawings and in combination with the embodiments.

[0021] As analyzed in the background technology of the present application, the preparation method of 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound in the prior art has the problem of high cost. In order to solve this problem, the present application provides a 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound and a preparation method thereof.

[0022] In a typical embodiment of the present application, a method for preparing 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is provided, and the method comprises: step S1, subjecting a raw material comprising 1,2,3-trifluoro-6-nitrobenzene and a cyaniding agent to a cyanolysis reaction to obtain 2,3-difluoro-6-nitro-benzonitrile; step S2, subjecting 2,3-difluoro-6-nitro-benzonitrile to a hydrogenation reduction reaction to obtain 2,3-difluoro-6-amino-benzonitrile; step S3, subjecting 2,3-difluoro-6-amino-benzonitrile to a diazotization reaction with a diazotization agent to obtain a diazonium salt; and step S4, subjecting the diazonium salt to a trifluoromethylation reaction with a trifluoromethylating agent to obtain 2,3-difluoro-6-(trifluoromethyl)-benzonitrile.

[0023] The present invention uses 1,2,3-trifluoro-6-nitrobenzene as a raw material, first reacts with cuprous cyanide or sodium cyanide to obtain 2,3-difluoro-6-nitro-benzonitrile, then hydrogenates to obtain 2,3-difluoro-6-amino-benzonitrile, and then performs a diazotization reaction and a trifluoromethylation reaction to prepare 2,3-difluoro-6-(trifluoromethyl)-benzonitrile. The above preparation method of the present application uses cheap 1,2,3-trifluoro-6-nitrobenzene as a raw material, and through the above reaction steps under mild reaction conditions, a high-yield 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound is obtained simply, quickly and at low cost, and is more suitable for industrial production.

[0024] In one embodiment of the present application, in the above step S1, the cyaniding agent is sodium cyanide and / or potassium cyanide, and preferably the molar ratio of the cyaniding agent to 1,2,3-trifluoro-6-nitrobenzene is 1.1 to 1.5:1.

[0025] The above cyaniding reagent is more helpful to promote the cyanolysis reaction between it and 1,2,3-trifluoro-6-nitrobenzene. The preferred molar ratio of the cyaniding reagent to 1,2,3-trifluoro-6-nitrobenzene is within the above range, such as 1.1:1, 1.2:1, 1.3:1, 1.4:1 or 1.5:1, so that the excess cyaniding reagent is more conducive to increasing the conversion rate of 1,2,3-trifluoro-6-nitrobenzene as much as possible.

[0026] In one embodiment of the present application, in the above step S1, the raw material also includes a first catalyst, and preferably the molar number of the first catalyst is 5-10% of the molar number of 1,2,3-trifluoro-6-nitrobenzene, and preferably the first catalyst is cuprous iodide.

[0027] Under the catalytic action of the above catalyst content (such as the molar number of the first catalyst is 5%, 6%, 7%, 8%, 9% or 10% of the molar number of 1,2,3-trifluoro-6-nitrobenzene), the efficiency and effect of the cyanolysis reaction between 1,2,3-trifluoro-6-nitrobenzene and the cyaniding agent are improved.

[0028] In one embodiment of the present application, in the above step S1, the raw material also includes a phase transfer catalyst, and the molar number of the phase transfer catalyst is preferably 10 to 30% of the molar number of 1,2,3-trifluoro-6-nitrobenzene, and the molar ratio of the first catalyst to the phase transfer catalyst is preferably 0.16 to 0.5:1, and the phase transfer catalyst is preferably tetrabutylammonium bromide and / or tetrabutylammonium chloride.

[0029] Adding a phase transfer catalyst (such as the molar number of the phase transfer catalyst is 10%, 15%, 20%, 25% or 30% of the molar number of 1,2,3-trifluoro-6-nitrobenzene) as a co-catalyst helps to promote the further progress of the cyanolysis reaction. The preferred type of the phase transfer catalyst and the molar ratio of the first catalyst to the phase transfer catalyst (such as 0.16:1, 0.2:1, 0.25:1, 0.3:1, 0.35:1, 0.4:1, 0.45:1 or 0.5:1) are more helpful to improve the synergistic catalytic effect of the first catalyst and the phase transfer catalyst, so that the yield of the target product of the cyanolysis reaction is higher, while the yield of the isomerized by-product is reduced.

[0030] In some embodiments of the present application, in the above step S1, the cyanolysis reaction is preferably carried out in a solvent, and the solvent is preferably selected from any one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-pyrrolidone. The cyanolysis reaction temperature is preferably 20 to 50°C, and the cyanolysis reaction time is preferably 12 to 24 hours, thereby helping to improve the efficiency and effect of the cyanolysis reaction and obtain 2,3-difluoro-6-nitro-benzonitrile with high yield and high purity as much as possible.

[0031] Since the cyanolysis reaction will inevitably generate isomers of the target product 2,3-difluoro-6-nitro-benzonitrile, especially the higher the reaction temperature, the more the nitro para-position substitution of 1,2,3-trifluoro-6-nitrobenzene is, and the more isomers are generated, the addition of the first catalyst and the phase transfer catalyst can help the cyanolysis reaction to have a higher reaction rate and high selectivity at a lower temperature than the cyanolysis reaction.

[0032] In some embodiments of the present application, in the above step S2, the hydrogenation reduction reaction is preferably carried out under the action of a second catalyst, and the molar number of the second catalyst is preferably 0.001 to 0.005 times the mass of 2,3-difluoro-6-nitro-benzonitrile. The second catalyst is preferably selected from any one or more of 3% palladium carbon, 1% palladium carbon, and 5% palladium carbon, so as to help improve the efficiency and effect of the hydrogenation reduction reaction.

[0033] In one embodiment of the present application, in the above step S2, the hydrogen partial pressure of the hydrogenation reduction reaction is 0.1-0.5 MPa, the temperature of the hydrogenation reduction reaction is preferably 20-25° C., and the time of the hydrogenation reduction reaction is preferably 8-24 hours. The above hydrogenation reduction reaction conditions are preferably helpful to improve the efficiency and effect of the hydrogenation reduction reaction, and the hydrogenation reduction reaction is preferably carried out in toluene or other solvents.

[0034] In one embodiment of the present application, in the above step S4, the diazotization reagent is selected from any one or more of sodium nitrite, tert-butyl nitroso ester, and tert-amyl nitroso ester. Preferably, the diazotization reagent is 1.1 to 1.3 times the molar number of 2,3-difluoro-6-amino-benzonitrile. Preferably, the pH value of the diazotization reaction is 1 to 3, and preferably the temperature of the diazotization reaction is 0 to 10°C.

[0035] The types and amounts of the above diazotization reagents are helpful to improve the efficiency of the diazotization reaction. The preferred temperature of the diazotization reaction is helpful to reduce the occurrence of side reactions as much as possible and improve the safety of the reaction. The pH value of the above diazotization reaction is preferably controlled within the above range by the addition of hydrochloric acid, thereby further improving the efficiency of the diazotization reaction.

[0036] In one embodiment of the present application, in the above step S4, the trifluoromethylation reagent is sodium trifluoromethylsulfinate and / or potassium trifluoromethylsulfinate, and the trifluoromethylation reagent is preferably 3 to 4 times the molar number of the diazonium salt; preferably, an oxidant is added in the trifluoromethylation reaction, and the amount of the oxidant added is preferably 2 to 3 times the molar number of the diazonium salt, and the oxidant is preferably tert-butyl peroxide; preferably, a third catalyst is added to catalyze the trifluoromethylation reaction, and the amount of the third catalyst added is preferably 2 to 3 times the molar number of the diazonium salt, and the third catalyst is preferably cuprous chloride and / or cuprous bromide; preferably, the pH value of the trifluoromethylation reaction is 1 to 3, and the temperature of the trifluoromethylation reaction is preferably 0 to 10°C.

[0037] The preferred type and amount of trifluoromethylation reagent, pH value and temperature of trifluoromethylation reaction are all helpful to improve the efficiency of trifluoromethylation of diazonium salt, and the addition of oxidant and third catalyst both improve the reaction activity of trifluoromethylation. Among them, based on the fact that diazotization reaction is carried out under acidic conditions, the pH value is regulated by adding alkaline substances such as sodium bicarbonate in the product system of diazonium salt.

[0038] In another typical embodiment of the present application, a 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound is provided. The 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound is prepared by the above preparation method.

[0039] The above preparation method of the present application is simple, fast and low-cost to obtain a high-yield 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound. Hydroxylamine hydrochloride is used as an oximation agent and anhydrous methanol is used as a solvent. The 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound is synthesized into 2,3-difluoro-N-hydroxy-6-(trifluoromethyl)benzamide through oximation. The yield after crystallization and purification can reach 80%, thereby greatly reducing the preparation cost of N'-(cyclopropylmethoxy)benzamide oxime pesticide compounds.

[0040] The beneficial effects of the present application will be further illustrated below in conjunction with embodiments.

[0041] Example 1

[0042] Step 1: Cyanide

[0043]

[0044] Add 50g of 1,2,3-trifluoro-6-nitrobenzene (0.282mol) and 200mL of DMF to a 500mL three-necked flask. After nitrogen replacement, stir to dissolve, control the temperature below 20°C, add 20.8g of sodium cyanide (0.424mol), and stir to react for 12 hours. After the sampling is qualified, control the temperature below 90°C and vacuum concentrate the solvent. After the solid is dissolved with 200g of ethyl acetate, wash it with 50g of water several times to pH=7, control the temperature below 80°C and concentrate the solvent. Purify it with a mixed solvent of petroleum ether 90-120: ethyl acetate = 20:1 through 15g of chromatographic silica gel 60-100 mesh, concentrate the solvent, and obtain 36.8g of 2,3-difluoro-6-nitro-benzonitrile qualified product, with a yield of 71% (theoretical yield: 51.9g).

[0045] Step 2: Hydrogenation

[0046]

[0047] Add 50g of 2,3-difluoro-6-nitro-benzonitrile (0.271mol), 200g of toluene, and 0.05g of 3% palladium carbon to a 2L stainless steel hydrogenation kettle. After the addition, replace the high-pressure hydrogenation kettle with 0.1MPa nitrogen three times, check for leaks, and after confirming that there is no leakage, replace the high-pressure hydrogenation kettle with 0.1MPa hydrogen three times, and then control the temperature at 20-25°C and hydrogenate at 0.1MPa for 24 hours. Take samples, replace them with 0.1MPa nitrogen three times after passing the test, disassemble the hydrogenation kettle after pressure relief, pour out the hydrogenation liquid, and rinse the inner wall of the hydrogenation kettle with a small amount of toluene. After passing the test, filter out the palladium carbon with filter paper, immerse the palladium carbon with water, install it, and control the temperature of the filtrate below 80°C to concentrate the solvent to obtain 50g of 2,3-difluoro-6-amino-benzonitrile crude product, with a yield of 100% (theoretical yield: 50g).

[0048] Steps 3 and 4: Diazotization and trifluoromethylation

[0049]

[0050] Add 20g of crude 2,3-difluoro-6-amino-benzonitrile (0.13mol) and 33.9g of 28% hydrochloric acid solution (0.26mol) to a 500mL three-necked flask at 0℃, and stir to react for 1 minute. Slowly add 9.9g of sodium nitrite (0.143mol) at 0℃, and continue to react at 0℃ for 20 minutes to form a diazonium salt.

[0051] Prepare another 500mL three-necked flask, add 8.7g sodium bicarbonate (0.104mol), 60.8g sodium trifluoromethylsulfinate (0.39mol), 7.7g cuprous chloride (0.078mol), 29g tert-butyl peroxide (0.325mol), and 50mL acetonitrile into the three-necked flask, and stir evenly. Add diazonium salt at 0℃, and after the addition, keep the temperature at 0℃ for 20 hours. After the reaction is complete, filter with a layer of diatomaceous earth on the filter paper, and wash the filtrate with 50mL of 10% brine until it is neutral. The reaction solution is concentrated at a temperature below 70℃ to obtain 22.8g of crude 2,3-difluoro-6-(trifluoromethyl)-benzonitrile, with a yield of 85% (theoretical yield: 26.9g). Its mass spectrum is shown as follows Figure 1 (Tested by gas chromatography-mass spectrometry) Figure 1 It can be seen that 207.1 is the molecular ion peak of 2,3-difluoro-6-(trifluoromethyl)-benzonitrile.

[0052] Example 2

[0053] The difference from Example 1 is that in the cyanolysis step, the amount of 1,2,3-trifluoro-6-nitrobenzene added remains unchanged, the molar ratio of sodium cyanide to 1,2,3-trifluoro-6-nitrobenzene is 1.1:1, and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is finally obtained.

[0054] Example 3

[0055] The difference from Example 1 is that in the cyanolysis step, the amount of 1,2,3-trifluoro-6-nitrobenzene added remains unchanged, the molar ratio of sodium cyanide to 1,2,3-trifluoro-6-nitrobenzene is 1:1, and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is finally obtained.

[0056] Example 4

[0057] The difference from Example 1 is that in the cyanolysis step, the amount of 1,2,3-trifluoro-6-nitrobenzene added remains unchanged, and 5% cuprous iodide is added to finally obtain 2,3-difluoro-6-(trifluoromethyl)-benzonitrile.

[0058] Example 5

[0059] The difference from Example 1 is that in the cyanolysis step, the amount of 1,2,3-trifluoro-6-nitrobenzene added remains unchanged, 10% of cuprous iodide is added, 10% of tetrabutylammonium bromide is added, and the molar ratio of cuprous iodide to tetrabutylammonium bromide is 1:1, and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is finally obtained.

[0060] Example 6

[0061] The difference from Example 1 is that in the cyanolysis step, the amount of 1,2,3-trifluoro-6-nitrobenzene added remains unchanged, 10% of cuprous iodide is added, 20% of tetrabutylammonium bromide is added, and the molar ratio of cuprous iodide to tetrabutylammonium bromide is 1:2, and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is finally obtained.

[0062] Example 7

[0063] The difference from Example 1 is that in the cyanolysis step, the amount of 1,2,3-trifluoro-6-nitrobenzene added remains unchanged, 10% of cuprous iodide is added, 30% of tetrabutylammonium bromide is added, and the molar ratio of cuprous iodide to tetrabutylammonium bromide is 1:3, and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is finally obtained.

[0064] Example 8

[0065] The difference from Example 1 is that in the cyanolysis step, the temperature of the cyanolysis reaction is 15° C., and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is finally obtained.

[0066] Example 9

[0067] The difference from Example 1 is that in the cyanolysis step, the temperature of the cyanolysis reaction is 50° C., and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is finally obtained.

[0068] Example 10

[0069] The difference from Example 1 is that in the hydrogenation step, the amount of hydrogenated 2,3-difluoro-6-nitro-benzonitrile remains unchanged, 3% palladium carbon is 0.003 times the mass of 2,3-difluoro-6-nitro-benzonitrile, the hydrogenation time is 17 hours, and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is finally obtained.

[0070] Embodiment 11

[0071] The difference from Example 1 is that in the hydrogenation step, the amount of 2,3-difluoro-6-nitro-benzonitrile remains unchanged, the hydrogen partial pressure is 0.5 MPa, the temperature of the hydrogenation reduction reaction is 25°C, the hydrogenation time is 8 hours, and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is finally obtained.

[0072] Example 12

[0073] The difference from Example 1 is that in the diazotization step, the amount of 2,3-difluoro-6-amino-benzonitrile remains unchanged, and the amount of sodium nitrite is 1.2 times the amount of 2,3-difluoro-6-amino-benzonitrile, and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is finally obtained.

[0074] Example 13

[0075] The difference from Example 1 is that in the diazotization step, the amount of 2,3-difluoro-6-amino-benzonitrile remains unchanged, and the amount of sodium nitrite is 1.3 times the amount of 2,3-difluoro-6-amino-benzonitrile, and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is finally obtained.

[0076] Embodiment 14

[0077] The difference from Example 1 is that in the diazotization step, the amount of 2,3-difluoro-6-amino-benzonitrile remains unchanged, the diazotization reagent is tert-pentyl nitrosoester, and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is finally obtained.

[0078] Embodiment 15

[0079] The difference from Example 1 is that in the trifluoromethylation step, the amount of diazonium salt remains unchanged, the pH value of the trifluoromethylation reaction is 3, the temperature of the trifluoromethylation reaction is 0°C, and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is finally obtained.

[0080] Example 16

[0081] The difference from Example 1 is that in the trifluoromethylation step, the amount of the diazonium salt remains unchanged, and the molar number of sodium trifluoromethylsulfinate is twice that of the diazonium salt, and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is finally obtained.

[0082] Embodiment 17

[0083] The difference from Example 1 is that in the trifluoromethylation step, the amount of the diazonium salt remains unchanged, and the molar number of tert-butyl peroxide is twice that of the diazonium salt, and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile is finally obtained.

[0084] The yields of 2,3-difluoro-6-nitro-benzonitrile, 2,3-difluoro-6-amino-benzonitrile and 2,3-difluoro-6-(trifluoromethyl)-benzonitrile in the above Examples 1 to 17 are listed in Table 1, respectively.

[0085] Table 1

[0086]

[0087]

[0088] From the above description, it can be seen that the above embodiments of the present invention achieve the following technical effects:

[0089] The present invention uses 1,2,3-trifluoro-6-nitrobenzene as a raw material, first reacts with cuprous cyanide or sodium cyanide to obtain 2,3-difluoro-6-nitro-benzonitrile, then hydrogenates to obtain 2,3-difluoro-6-amino-benzonitrile, and then performs a diazotization reaction and a trifluoromethylation reaction to prepare 2,3-difluoro-6-(trifluoromethyl)-benzonitrile. The above preparation method of the present application uses cheap 1,2,3-trifluoro-6-nitrobenzene as a raw material, and through the above reaction steps under mild reaction conditions, a high-yield 2,3-difluoro-6-(trifluoromethyl)-benzonitrile compound is obtained simply, quickly and at low cost, and is more suitable for industrial production.

[0090] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing 2,3-difluoro-6-(trifluoromethyl)-benzonitrile, characterized in that: The preparation method comprises: Step S1, subjecting a raw material including 1,2,3-trifluoro-6-nitrobenzene and a cyaniding agent to a cyanolysis reaction to obtain 2,3-difluoro-6-nitro-benzonitrile; Step S2, subjecting the 2,3-difluoro-6-nitro-benzonitrile to a hydrogenation reduction reaction to obtain 2,3-difluoro-6-amino-benzonitrile; Step S3, the 2,3-difluoro-6-amino-benzonitrile is subjected to a diazotization reaction with a diazotizing agent to obtain a diazonium salt; and Step S4, the diazonium salt is subjected to a trifluoromethylation reaction with a trifluoromethylating agent to obtain 2,3-difluoro-6-(trifluoromethyl)-benzonitrile; Wherein, the cyaniding agent is sodium cyanide and / or potassium cyanide, and the temperature of the cyanolysis reaction is 20 to 50°C; The hydrogen partial pressure of the hydrogenation reduction reaction is 0.1-0.5 MPa, and the temperature of the hydrogenation reduction reaction is 20-25°C; The diazotization reagent is selected from any one or more of sodium nitrite, tert-butyl nitroso ester, and tert-amyl nitroso ester, the pH value of the diazotization reaction is 1 to 3, and the temperature of the diazotization reaction is 0 to 10° C.; The trifluoromethylation reagent is sodium trifluoromethylsulfinate and / or potassium trifluoromethylsulfinate; the pH value of the trifluoromethylation reaction is 1 to 3, and the temperature of the trifluoromethylation reaction is 0 to 10°C; Adding an oxidant in the trifluoromethylation reaction, wherein the oxidant is tert-butyl peroxide; A trifluoromethylation reaction catalyst is added to catalyze the trifluoromethylation reaction, and the trifluoromethylation reaction catalyst is cuprous chloride and / or cuprous bromide.

2. The preparation method according to claim 1, characterized in that: In the step S1, the molar ratio of the cyaniding agent to the 1,2,3-trifluoro-6-nitrobenzene is 1.1-1.5:

1.

3. The preparation method according to claim 1 or 2, characterized in that: In the step S1, the raw material also includes a cyanolysis reaction catalyst.

4. The preparation method according to claim 3, characterized in that: The molar number of the cyanolysis reaction catalyst is 5-10% of the molar number of the 1,2,3-trifluoro-6-nitrobenzene.

5. The preparation method according to claim 3, characterized in that: The cyanolysis reaction catalyst is cuprous iodide.

6. The preparation method according to claim 3, characterized in that: In the step S1, the raw material further includes a phase transfer catalyst.

7. The preparation method according to claim 6, characterized in that: In the step S1, the molar number of the phase transfer catalyst is 10-30% of the molar number of the 1,2,3-trifluoro-6-nitrobenzene.

8. The preparation method according to claim 6, characterized in that: In the step S1, the molar ratio of the cyanolysis reaction catalyst to the phase transfer catalyst is 0.16-0.5:

1.

9. The preparation method according to claim 6, characterized in that: In the step S1, the phase transfer catalyst is tetrabutylammonium bromide and / or tetrabutylammonium chloride.

10. The preparation method according to claim 1, characterized in that: In the step S1, the cyanolysis reaction is carried out in a solvent.

11. The preparation method according to claim 10, characterized in that: The solvent is selected from any one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-pyrrolidone.

12. The preparation method according to claim 10, characterized in that: The cyanolysis reaction time is 12 to 24 hours.

13. The preparation method according to claim 1, characterized in that: In the step S2, the hydrogenation reduction reaction is carried out under the action of a hydrogenation reduction reaction catalyst.

14. The preparation method according to claim 13, characterized in that: The molar number of the hydrogenation reduction reaction catalyst is 0.001 to 0.005 times the mass of the 2,3-difluoro-6-nitro-benzonitrile substance.

15. The preparation method according to claim 13, characterized in that: The hydrogenation reduction reaction catalyst is selected from any one or more of 3% palladium carbon, 1% palladium carbon, and 5% palladium carbon.

16. The preparation method according to claim 1, characterized in that: In the step S2, the hydrogenation reduction reaction time is 8 to 24 hours.

17. The preparation method according to claim 1, characterized in that: The molar number of the diazotizing agent is 1.1 to 1.3 times that of the 2,3-difluoro-6-amino-benzonitrile.

18. The preparation method according to claim 1, characterized in that: In the step S4, the molar amount of the trifluoromethylation reagent is 2 to 4 times that of the diazonium salt.

19. The preparation method according to claim 1, characterized in that: The added amount of the oxidant is 2 to 3 times the molar number of the diazonium salt.

20. The preparation method according to claim 1, characterized in that: The added amount of the trifluoromethylation reaction catalyst is 2 to 3 times the molar number of the diazonium salt.

Images