Preparation process of 4-bromo-2,6-difluorobenzonitrile

Abstract

The present invention belongs to the technical field of pharmaceutical synthesis and preparation, and provides a preparation process of 4-bromo-2,6-difluorobenzonitrile. The preparation process uses 3,5-difluorobromobenzene as a raw material, undergoes a deprotonation reaction with a non-nucleophilic strong base, and condenses with dry ice to obtain 4-bromo-2,6-difluorobenzoic acid; then undergoes amidation to obtain 4-bromo-2,6-difluorobenzamide, and finally undergoes amide dehydration to obtain the target product 4-bromo-2,6-difluorobenzonitrile. This preparation process has the advantages of low cost, high molar yield, low operation difficulty, easy industrial production, low toxicity and small pollution.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis and preparation, and provides a preparation process of 4-bromo-2,6-difluorobenzonitrile. Background Art

[0002] 4-Bromo-2,6-difluorobenzonitrile, an organic synthesis intermediate and a pharmaceutical intermediate, is mainly used in the laboratory R & D process and the chemical production process; currently, it is widely used as an intermediate compound in the preparation of liquid crystal materials, and its structural formula is as follows:

[0003]

[0004] The production process of 4-bromo-2,6-difluorobenzonitrile generally uses 2,6-difluoroaniline as a raw material, and needs to synthesize the liquid crystal intermediate 4-bromo-2,6-difluorobenzonitrile through bromination, diazotization and Sandmeyer reaction.

[0005] Gray, G et al. published a synthesis route of 4-bromo-2,6-difluorobenzonitrile in Molecular Crystals and Liquid Crystals (1989, 172, 165-190), which is specifically as follows:

[0006]

[0007] This route has a complex technical process, and bromine, potassium cyanide, and concentrated sulfuric acid are used in the raw materials. They not only have extremely strong corrosiveness, but also high toxicity. The environmental pollution is serious during production, and its cost is high, and the yield is only 30%.

[0008] The invention patent CA2534127A1 discloses that using 4-bromo-2,6-difluorobenzamide as a raw material, reacting with 1,3,5-trichloro-2,4,6-triazine in a DMF (N,N-dimethylformamide) solution at 0 °C for 3 hours to prepare 4-bromo-2,6-difluorobenzonitrile, and the yield is 86.9%.

[0009] The Chinese invention patent CN101353317B discloses another production route, using 3,5-difluorobromobenzene as a reaction raw material and N,N-dimethylformamide as an aldehyde reagent, under the catalysis of butyllithium for hydrogen abstraction, synthesizing 4-bromo-2,6-difluorobenzaldehyde, and then dehydrating with hydroxylamine hydrochloride and formic acid to obtain 4-bromo-2,6-difluorobenzonitrile. The specific synthesis route is as follows:

[0010]

[0011] This route uses inexpensive 3,5-difluorobromobenzene as the reaction raw material, which not only greatly saves costs but also avoids the use of highly toxic potassium cyanide and strongly corrosive substances such as sulfuric acid and bromine, reducing environmental pollution. However, the intermediate benzaldehyde compounds have poor stability and low yields. Summary of the Invention

[0012] To solve the problems of low yield of 4-bromo-2,6-difluorobenzonitrile in the prior art, avoid the use of toxic and harmful raw materials such as bromine, potassium cyanide, and acetonitrile, and effectively reduce production costs, the present invention provides a preparation process for 4-bromo-2,6-difluorobenzonitrile using 3,5-difluorobromobenzene as the raw material. The raw materials and auxiliary materials are inexpensive, the synthesis route is mature, the operation is simple, the molar yield is high, and the product has high purity, which is suitable for industrial scale-up production.

[0013] The technical solution of the present invention is as follows:

[0014] The present invention provides a synthesis route for preparing 4-bromo-2,6-difluorobenzonitrile using 3,5-difluorobromobenzene as the raw material as follows:

[0015]

[0016] Specifically, it includes the following steps:

[0017] (1) Using 3,5-difluorobromobenzene as the raw material, a hydrogen abstraction reaction is carried out under the action of a non-nucleophilic strong base reagent, and then a condensation reaction is carried out with dry ice to obtain 4-bromo-2,6-difluorobenzoic acid;

[0018] (2) 4-bromo-2,6-difluorobenzoic acid undergoes an amidation reaction to obtain 4-bromo-2,6-difluorobenzamide;

[0019] (3) 4-bromo-2,6-difluorobenzamide undergoes a dehydration reaction to obtain 4-bromo-2,6-difluorobenzonitrile.

[0020] In some embodiments of the present invention, in step (1), after the condensation reaction is completed, the reaction solution is extracted to obtain 4-bromo-2,6-difluorobenzoic acid.

[0021] In some embodiments of the present invention, in step (3), after the dehydration reaction is completed, the reaction solution is extracted to obtain 4-bromo-2,6-difluorobenzonitrile.

[0022] In some embodiments of the present invention, the extraction solvent used in the extraction in step (1) and step (3) is selected from any one of methyl tert-butyl ether, ethyl acetate, and dichloromethane.

[0023] In some embodiments of the present invention, during the amination process of the amidation reaction in step (2), the intermediate acyl compound is added dropwise to the amination reagent ammonia water. Compared with adding ammonia water to the intermediate acyl compound, the reaction is more complete, further improving the yield.

[0024] In some embodiments of the present invention, the molar ratio of 3,5-difluorobromobenzene to the non-nucleophilic strong base reagent is 1:1.2 - 1.8; the molar ratio of 3,5-difluorobromobenzene to dry ice is 1:2 - 10.

[0025] Further, the amidation reaction described in step (2) further includes an acylation process and an amination process.

[0026] In some embodiments of the present invention, during the acylation process, the mass-volume ratio of 4-bromo-2,6-difluorobenzoic acid to the acylation reagent is 1:2 - 10 g / mL; during the amination process, the mass-volume ratio of 4-bromo-2,6-difluorobenzoic acid to the amination reagent is 1:2 - 10 g / mL.

[0027] In some embodiments of the present invention, the mass-volume ratio of 4-bromo-2,6-difluorobenzamide to the dehydration reagent is 1:4 - 8 g / mL.

[0028] In some embodiments of the present invention, the non-nucleophilic strong base reagent is selected from any one of n-butyllithium, lithium diethylamide, lithium diisopropylamide, and lithium bis(trimethylsilyl)amide.

[0029] In some embodiments of the present invention, the acylation reagent is selected from any one of chlorine gas, triphosgene, thionyl chloride, trifluoroacetic anhydride, phosphorus oxychloride, N-chlorosuccinimide, sodium hypochlorite, and phosphorus pentachloride.

[0030] In some embodiments of the present invention, the amination reagent is ammonia water.

[0031] In some embodiments of the present invention, the dehydration reagent is selected from any one of thionyl chloride, phosphorus oxychloride, phosphorus pentoxide, phosphorus pentachloride, trifluoroacetic anhydride, acetic anhydride, and tin(IV) chloride.

[0032] In some embodiments of the present invention, the temperature of the hydrogen abstraction reaction is -78 to -30 °C, and the reaction time is 2 - 4 h; the temperature of the condensation reaction is -50 to 30 °C.

[0033] In some embodiments of the present invention, the temperature of the acylation process is 30 - 80 °C, and the time is 2 - 5 h; the temperature of the amination process is 0 - 10 °C, and the time is 0.5 - 3 h.

[0034] In some embodiments of the present invention, the temperature of the dehydration reaction is 50 - 80 °C, and the reaction time is 1 - 8 h.

[0035] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0036] 1. Compared with the prior art, the present invention replaces benzaldehyde with benzoic acid with higher stability. During the synthesis of 4-bromo-2,6-benzenedicarboxylic acid, almost no impurities are generated, improving the purity of the product.

[0037] 2. Using dry ice as the condensation reactant not only solves the temperature control problem during condensation, avoids the generation of new impurities, but also enables the reaction solution to be quickly exposed to a high concentration of CO 2 in, greatly shortening the reaction time, making the reaction purity up to more than 95%, and no additional purification treatment is required.

[0038] 3. Optimize the ratio of each reactant during the reaction process, promote the reaction process, and greatly improve the yield; and optimize the feeding order, especially in the amination reaction, adding the raw materials to ammonia water, further improving the yield. The total molar yield of the three-step reaction is above 84%.

[0039] 4. The reaction treatment is simple, the solvent can be recycled and reused, realizing resource reuse.

[0040] 5. The raw and auxiliary materials of the present invention have low cost, saving production costs; at the same time, the operation is simple, suitable for industrial scale-up production; low toxicity and little environmental pollution. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 is the synthetic route diagram of 4-bromo-2,6-difluorobenzonitrile;

[0042] Figure 2 is the HPLC chromatogram of 4-bromo-2,6-difluorobenzoic acid in Example 1;

[0043] Figure 3 is the 1H NMR spectrum of 4-bromo-2,6-difluorobenzoic acid in Example 1;

[0044] Figure 4 is the HPLC chromatogram of 4-bromo-2,6-difluorobenzamide in Example 1;

[0045] Figure 5 is the 1H NMR spectrum of 4-bromo-2,6-difluorobenzamide in Example 1;

[0046] Figure 6 is the HPLC chromatogram of 4-bromo-2,6-difluorobenzonitrile in Example 1;

[0047] Figure 7 is the 1H NMR spectrum of 4-bromo-2,6-difluorobenzonitrile in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0048] The following non-limiting examples can enable those of ordinary skill in the art to more comprehensively understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary illustration of the scope claimed by the present invention. Those skilled in the art can make various changes and modifications to the invention based on the disclosed content, and these should also fall within the scope claimed by the present invention. It is worth noting that the raw materials used in the present invention are all ordinary commercially available products, and no specific limitation is made on their sources.

[0049] Example 1

[0050] (1) Preparation of 4-bromo-2,6-difluorobenzoic acid

[0051] 100 g (0.518 mol) of 3,5-difluorobromobenzene and 1000 mL of tetrahydrofuran were put into a reaction flask and cooled to -78 °C. 248.6 mL (containing 0.622 mol of n-butyllithium) of n-butyllithium (2.5 M tetrahydrofuran solution) was added dropwise. After the addition, the reaction was kept at a constant temperature for 3 hours. Another reaction flask was prepared, 45.6 g (1.036 mol) of dry ice was added, and the above reaction solution of n-butyllithium was added dropwise to the dry ice. The reaction solution was heated to 10 °C and kept at a constant temperature for 8 hours. After the reaction, dilute hydrochloric acid was added to quench the reaction, and then methyl tert-butyl ether was added for extraction to obtain an aqueous layer and an organic layer. Methyl tert-butyl ether was added to the extracted aqueous layer again for secondary extraction. The two organic layers were combined, and saturated brine was added to wash the organic layer. The organic layer was concentrated and crystallized to obtain 116.7 g of white solid 4-bromo-2,6-difluorobenzoic acid, with a molar yield of 95%; the results of liquid chromatography are shown in Figure 2 : The purity was 98.6%; the results of 1H NMR are shown in Figure 3 : 1 1H NMR (400 MHz, CDCl 3 ) δ 7.19 - 7.23 (m, 1H), 5.10 (br, 1H);

[0052] (2) Preparation of 4-bromo-2,6-difluorobenzamide

[0053] 116.7 g of the 4-bromo-2,6-difluorobenzoic acid prepared above was taken, 233.4 mL of thionyl chloride was added, and the temperature was raised to 80 °C and reacted for 2 hours. After the reaction, thionyl chloride was removed by concentration to obtain an oily intermediate acyl compound. Another reaction flask was taken, 233.4 mL of 25% ammonia water was added, and the temperature was cooled to 10 °C. The intermediate acyl compound was added dropwise to the ammonia water at a controlled temperature of 10 °C. After the addition, the reaction was kept at a constant temperature of 10 °C for 2 hours. After filtration and drying, 115 g of light yellow solid 4-bromo-2,6-difluorobenzamide was obtained, with a molar yield of 99%; the results of liquid chromatography are shown in Figure 4 , purity: 99.2%; the results of 1H NMR are shown in Figure 5 : 1H NMR (400 MHz, CDCl3 ) δ 7.16 - 7.20 (m, 2H), 6.11 (d, 2H);

[0054] (3) Preparation of 4 - bromo - 2,6 - difluorobenzonitrile

[0055] Take 115 g of the 4 - bromo - 2,6 - difluorobenzamide prepared above, add 460 mL of thionyl chloride, heat up to 80 °C and react for 6 hours. Then concentrate to remove thionyl chloride, add 230 g of water to quench, and add methyl tert - butyl ether to extract the product. The aqueous layer is extracted with methyl tert - butyl ether for a second time. Combine the two organic layers of extraction, add 5.7 g of activated carbon for decolorization, filter and concentrate to crystallize to obtain 95.6 g of off - white solid 4 - bromo - 2,6 - difluorobenzonitrile, with a molar yield of 90%. The results of liquid chromatography are shown in Figure 6 , purity: 99.9%; The results of 1H NMR spectrum are shown in Figure 7 : 1H NMR (400 MHz, CDCl 3 ) δ 7.30 - 7.33 (m, 2H);

[0056] The total molar yield of the three steps is 84.65%.

[0057] Example 2

[0058] (1) Preparation of 4 - bromo - 2,6 - difluorobenzoic acid

[0059] Put 100 g (0.518 mol) of 3,5 - difluorobromobenzene and 1000 mL of tetrahydrofuran into a reaction flask, cool down to - 40 °C, and dropwise add 388.5 mL (containing 0.777 mol of lithium diisopropylamide) of lithium diisopropylamide solution (2 M in tetrahydrofuran). After the addition, keep the reaction at the same temperature for 3 hours. Prepare another reaction flask, add 114 g of dry ice (2.59 mol), and dropwise add the above - mentioned reaction solution of lithium diisopropylamide to the dry ice. Heat the reaction solution to 10 °C and keep the reaction for 8 hours. After the reaction, add dilute hydrochloric acid to quench, and then add dichloromethane for extraction to obtain an aqueous layer and an organic layer. Again, add dichloromethane to the extracted aqueous layer for a second extraction. Combine the two organic layers, add saturated brine to wash the organic layer, and concentrate and crystallize the organic layer to obtain 115 g of white solid 4 - bromo - 2,6 - difluorobenzoic acid, with a molar yield of 93.6%; Liquid phase purity: 98.9%;

[0060] (2) Preparation of 4 - bromo - 2,6 - difluorobenzamide

[0061] Take 115 g of the 4-bromo-2,6-difluorobenzoic acid prepared above, add 575 mL of trifluoroacetic anhydride, heat up to 40 °C and react for 4 hours. After the reaction is completed, concentrate to remove trifluoroacetic anhydride to obtain an oily substance as the intermediate acyl compound; Take another reaction flask, add 575 mL of 25% ammonia water, cool down to 10 °C, and dropwise add the intermediate acyl compound to the ammonia water at a controlled temperature of 10 °C. After the dropping is completed, keep the temperature at 10 °C and react for 2 hours. Filter and dry to obtain 112 g of pale yellow solid 4-bromo-2,6-difluorobenzamide, with a molar yield of 97.8%; Liquid phase purity: 99.1%;

[0062] (3) Preparation of 4-bromo-2,6-difluorobenzonitrile

[0063] Take 112 g of the 4-bromo-2,6-difluorobenzamide prepared above, add 672 mL of phosphorus oxychloride, heat up to 80 °C and react. After reacting for 8 hours, concentrate to remove phosphorus oxychloride, add 336 g of water to quench, then add dichloromethane to extract the product, and add dichloromethane to the aqueous layer for secondary extraction. Combine the two organic layers of extraction, add 5.6 g of activated carbon for decolorization, filter and concentrate to crystallize to obtain 96 g of off-white solid 4-bromo-2,6-difluorobenzonitrile, with a molar yield of 92.8%; Liquid phase purity: 99.8%;

[0064] The total molar yield of the three steps is 84.95%.

[0065] Example 3

[0066] (1) Preparation of 4-bromo-2,6-difluorobenzoic acid

[0067] Put 100 g (0.518 mol) of 3,5-difluorobromobenzene and 1000 mL of tetrahydrofuran into a reaction flask, cool down to -60 °C, and dropwise add 373 mL (containing 0.932 mol of n-butyllithium) of n-butyllithium (2.5 M tetrahydrofuran solution). After the dropping is completed, keep the temperature and react for 3 hours; Prepare another reaction flask, add 228 g (5.18 mol) of dry ice, and dropwise add the above reaction solution of n-butyllithium to the dry ice. Heat up the reaction solution to 10 °C and keep the temperature and react for 8 hours; After the reaction is completed, add dilute hydrochloric acid to quench, and then add methyl tert-butyl ether for extraction to obtain an aqueous layer and an organic layer; Add methyl tert-butyl ether to the extracted aqueous layer again for secondary extraction. Combine the two organic layers, add saturated brine to wash the organic layer, and concentrate and crystallize the organic layer to obtain 118.5 g of white solid 4-bromo-2,6-difluorobenzoic acid, with a molar yield of 96.5%; Liquid phase purity is 98.2%;

[0068] (2) Preparation of 4-bromo-2,6-difluorobenzamide

[0069] Take 118.5 g of the 4-bromo-2,6-difluorobenzoic acid prepared above, add 948 mL of phosphorus oxychloride, heat up to 80 °C and react for 5 hours. After the reaction is completed, concentrate to remove phosphorus oxychloride to obtain an oily substance as the intermediate acyl compound; Take another reaction flask, add 948 mL of 25% ammonia water, cool down to 10 °C, and dropwise add the intermediate acyl compound to the ammonia water at a controlled temperature of 10 °C. After the addition is completed, keep the temperature at 10 °C and react for 2 hours. Filter and dry to obtain 115.6 g of light yellow solid 4-bromo-2,6-difluorobenzamide, with a molar yield of 98%; Liquid phase purity: 98.9%;

[0070] (3) Preparation of 4-bromo-2,6-difluorobenzonitrile

[0071] Take 115.6 g of the 4-bromo-2,6-difluorobenzamide prepared above, add 924.8 mL of thionyl chloride, heat up to 50 °C and react for 6 hours. Concentrate to remove thionyl chloride, add 462.4 g of water to quench, then add methyl tert-butyl ether to extract the product. The aqueous layer is extracted again with methyl tert-butyl ether. Combine the two organic layers of extraction, add 5.7 g of activated carbon for decolorization, filter and concentrate to crystallize to obtain 95.0 g of off-white solid 4-bromo-2,6-difluorobenzonitrile, with a molar yield of 89%; Liquid phase purity: 99.8%;

[0072] The total molar yield of the three steps is 84.2%.

[0073] Comparative Example 1-1 Preparation of 4-bromo-2,6-difluorobenzoic acid

[0074] Put 100 g (0.518 mol) of 3,5-difluorobromobenzene and 1000 mL of tetrahydrofuran into a reaction flask and cool down to -78 °C. Dropwise add 622 mL (containing 1.554 mol of n-butyllithium) of n-butyllithium (2.5 M tetrahydrofuran solution). After the addition is completed, keep the temperature and react for 3 hours; Prepare another reaction flask, add 45.6 g (1.036 mol) of dry ice, and dropwise add the above reaction solution of n-butyllithium to the dry ice. Heat up the reaction solution to 10 °C and keep the temperature and react for 8 hours; After the reaction is completed, add dilute hydrochloric acid to quench, then add methyl tert-butyl ether for extraction to obtain an aqueous layer and an organic layer; Add methyl tert-butyl ether to the extracted aqueous layer again for secondary extraction. Combine the two organic layers, add saturated brine to wash the organic layer, and concentrate and crystallize the organic layer to obtain 101.3 g of light yellow solid 4-bromo-2,6-difluorobenzoic acid, with a molar yield of 82.5%; Purity is 85.2%; Comparative Example 1-2 Preparation of 4-bromo-2,6-difluorobenzamide

[0075] Take 101.3 g of 4-bromo-2,6-difluorobenzoic acid from step (1) of Example 1, add 202.6 mL of thionyl chloride, heat up to 80 °C and react for 2 hours. After the reaction is completed, concentrate to remove thionyl chloride to obtain an oily substance as the intermediate acyl compound; cool the intermediate acyl compound to 10 °C, control the temperature at 10 °C and directly add 202.6 mL of 25% ammonia water dropwise to the intermediate acyl compound. After the addition is completed, keep the temperature at 10 °C and react for 2 hours, filter and dry to obtain 45.8 g of pale yellow solid 4-bromo-2,6-difluorobenzamide, with a molar yield of 45.4%; purity: 61.4%;

[0076] Comparative Examples 1-3 Preparation of 4-bromo-2,6-difluorobenzonitrile

[0077] Take 45.8 g of 4-bromo-2,6-difluorobenzamide prepared in step (2) of Example 1, add 183.2 mL of thionyl chloride, heat up to 105 °C and reflux. After refluxing for 8 hours, concentrate to remove thionyl chloride, add 137.4 g of water to quench, then add methyl tert-butyl ether to extract the product, and add methyl tert-butyl ether to the aqueous layer for secondary extraction. Combine the two organic layers of extraction, add 5.7 g of activated carbon for decolorization, filter and concentrate to crystallize to obtain 17.0 g of yellowish-brown solid 4-bromo-2,6-difluorobenzonitrile, with a molar yield of 40.2%; purity: 52.3%;

[0078] The total three-step molar yield is 15.1%.

[0079] Comparative Example 2-1 Preparation of 4-bromo-2,6-difluorobenzoic acid

[0080] Put 100 g (0.518 mol) of 3,5-difluorobromobenzene and 1000 mL of tetrahydrofuran into a reaction flask, cool down to -78 °C, and dropwise add 248.6 mL (containing 0.622 mol of n-butyllithium) of n-butyllithium (2.5 M tetrahydrofuran solution). After the addition is completed, keep the temperature and react for 1 hour; prepare another reaction flask, add 228 g (5.18 mol) of dry ice, and dropwise add the above reaction solution of n-butyllithium to the dry ice. Heat the reaction solution to 5 °C and keep the temperature and react for 8 hours; after the reaction is completed, add dilute hydrochloric acid to quench, and then add methyl tert-butyl ether for extraction to obtain an aqueous layer and an organic layer; add methyl tert-butyl ether to the extracted aqueous layer again for secondary extraction. Combine the two organic layers, add saturated brine to wash the organic layer, and concentrate and crystallize the organic layer to obtain 99.1 g of pale yellow solid 4-bromo-2,6-difluorobenzoic acid, with a molar yield of 80.7%; purity is 82.1%;

[0081] Comparative Example 2-2 Preparation of 4-bromo-2,6-difluorobenzamide

[0082] Take 99.1 g of 4-bromo-2,6-difluorobenzoic acid from step (1) of Example 1, add 148.6 mL of thionyl chloride, heat up to 80 °C and react for 2 hours. After the reaction is completed, concentrate to remove thionyl chloride to obtain an oily substance as the intermediate acyl compound; take another reaction flask, add 198.2 mL of 25% ammonia water, cool down to 10 °C, and dropwise add the intermediate acyl compound to the ammonia water at a controlled temperature of 10 °C. After the addition is completed, keep the temperature at 10 °C and react for 2 hours. Filter and dry to obtain 65.3 g of yellow solid 4-bromo-2,6-difluorobenzamide, with a molar yield of 65.8%; purity: 76.1%;

[0083] Comparative Example 2-3 Preparation of 4-bromo-2,6-difluorobenzonitrile

[0084] Take 65.3 g of 4-bromo-2,6-difluorobenzamide prepared in step (2) of Example 1, add 130.6 mL of thionyl chloride, heat up to 80 °C and reflux. After refluxing for 6 hours, concentrate to remove thionyl chloride, add 130.6 g of water to quench, then add methyl tert-butyl ether to extract the product, and add methyl tert-butyl ether to the aqueous layer for secondary extraction. Combine the two organic layers of extraction, add 5.7 g of activated carbon for decolorization, filter and concentrate to crystallize to obtain 27.3 g of yellowish-brown solid 4-bromo-2,6-difluorobenzonitrile, with a molar yield of 45.2%, purity: 73.1%;

[0085] The total molar yield of the three steps is 24.0%.

[0086] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than a limitation on the protection scope of the present invention. Any simple modification or equivalent replacement of the technical solution of the present invention by those of ordinary skill in the art shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A preparation process of 4-bromo-2,6-difluorobenzonitrile, characterized in that, the reaction route is as follows: Specifically, it includes the following steps: (1) Using 3,5-difluorobromobenzene as a raw material, under the action of a non-nucleophilic strong base reagent, a hydrogen abstraction reaction is carried out at -78 to -30 °C for 2-4 h, and then a condensation reaction is carried out with dry ice to obtain 4-bromo-2,6-difluorobenzoic acid; (2) 4-bromo-2,6-difluorobenzoic acid undergoes an acylation reaction with an acylating reagent to obtain an intermediate acyl compound; then the intermediate acyl compound is added dropwise to an aminating reagent for an amination reaction to obtain 4-bromo-2,6-difluorobenzamide; (3) 4-bromo-2,6-difluorobenzamide undergoes a dehydration reaction with a dehydrating reagent at 50-80 °C for 1-8 h to obtain 4-bromo-2,6-difluorobenzonitrile; The non-nucleophilic strong base reagent is any one of n-butyllithium, lithium diethylamide, lithium diisopropylamide, and lithium bis(trimethylsilyl)amide; the molar ratio of 3,5-difluorobromobenzene to the non-nucleophilic strong base reagent is 1:1.2-1.8; In the acylation process, the mass-volume ratio of 4-bromo-2,6-difluorobenzoic acid to the acylating reagent is 1:2-10 g / mL; In the dehydration reaction, the mass-volume ratio of 4-bromo-2,6-difluorobenzamide to the dehydrating reagent is 1:4-8 g / mL.

2. The preparation process according to claim 1, characterized in that, the molar ratio of 3,5-difluorobromobenzene to dry ice is 1:2-10.

3. The preparation process according to claim 1, characterized in that, in the amination process, the mass-volume ratio of 4-bromo-2,6-difluorobenzoic acid to the aminating reagent is 1:2-10 g / mL.

4. The preparation process according to claim 1, characterized in that, the acylating reagent is selected from any one of chlorine gas, triphosgene, thionyl chloride, trifluoroacetic anhydride, phosphorus oxychloride, N-chlorosuccinimide, sodium hypochlorite, and phosphorus pentachloride; the aminating reagent is ammonia water.

5. The preparation process according to claim 1, characterized in that, the dehydrating reagent is selected from any one of thionyl chloride, phosphorus oxychloride, phosphorus pentoxide, phosphorus pentachloride, trifluoroacetic anhydride, acetic anhydride, and tin tetrachloride.

6. The preparation process according to claim 1, characterized in that, the temperature of the condensation reaction is -50 to 30 °C.

7. The preparation process according to claim 1, characterized in that, in the amidation reaction, the temperature of the acylation process is 30-80 °C and the time is 2-5 h; the temperature of the amination process is 0-10 °C and the time is 0.5-3 h.

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