One-pot preparation of 3,4,5-trifluorobromobenzene

Abstract

The application discloses a one-pot preparation method of 3,4,5-trifluorobromobenzene. In an organic solvent, 2,6-difluoroaniline is used as raw material to obtain the product 3,4,5-trifluorobromobenzene through three steps of bromination, diazotization and fluorination at a certain temperature. The method has the advantages of multiple raw material sources, obvious cost advantage, safety and convenience, high total yield, less waste and the like, and is beneficial to industrialization.

Description

Technical Field

[0001] This invention relates to a one-pot method for preparing 3,4,5-trifluorobromobenzene, specifically a method for obtaining the product 3,4,5-trifluorobromobenzene through a three-step reaction of bromination, diazotization, and fluorination using 2,6-difluoroaniline as a raw material. Background Technology

[0002] 3,4,5-Trifluorobromobenzene is an important intermediate in the SDHI fungicide fluopyram. Fluopyram is an amide fungicide developed by BASF and is also a succinate dehydrogenase inhibitor. It is mainly used on grains, soybeans, corn, vegetables, fruits, and cash crops for foliar or seed treatment to control various diseases. The literature reports two main methods for synthesizing 3,4,5-trifluorobromobenzene: 1. Preparation via fluorination and bromination of 1,2,3-trichlorobenzene; 2. Preparation via nitration, reduction, bromination, and diazotization of 1,2,3-trichlorobenzene for denitrification. The first method has poor selectivity in bromination, producing a large proportion of isomers, resulting in low separation yield and increased cost. The second method improves selectivity by adding amino groups, but this increases the number of steps, reduces yield, increases cost, and generates more waste. Furthermore, safety and production capacity per unit time are difficult to control; large-scale production is also more expensive. Summary of the Invention

[0003] The technical problem this invention aims to solve is to address the shortcomings of existing technologies by providing a method for preparing 3,4,5-trifluorobromobenzene. In an organic solvent at a certain temperature, 3,4,5-trifluorobromobenzene is obtained through a three-step reaction involving bromination, diazotization, and fluorination using 2,6-difluoroaniline as a raw material. This method offers advantages such as diverse raw material sources, significant cost savings, safer and more convenient preparation, high overall yield, and reduced waste, making it suitable for industrial application.

[0004] To achieve the above objectives, the present invention adopts the following technical solution:

[0005] A method for preparing a 4-cyclopropyl-substituted benzoic acid analog includes the following steps:

[0006] (1) In an organic solvent, 2,6-difluoroaniline and brominating reagent and catalyst A are added at a certain temperature to carry out a bromination reaction to obtain product 2,6-difluoro-4-bromoaniline intermediate I;

[0007] (2) In an organic solvent, 2,6-difluoro-4-bromoaniline intermediate I, diazotizing agent, and fluorinating agent are added at a certain temperature and reacted in a one-pot manner to obtain the product 3,4,5-trifluorobromobenzene;

[0008] The reaction formula is: ;

[0009] The preparation method in the above technical solution is as follows:

[0010] (1) Under nitrogen protection, organic solvent, 2,6-difluoroaniline, brominating reagent and catalyst A are added to the reaction vessel in sequence. After stirring evenly, the mixture is raised to the set temperature. The mixture is kept at this temperature until the normalized content of 2,6-difluoroaniline in the total material is <1% by liquid chromatography. 2,6-difluoro-4-bromoaniline intermediate I solution is obtained.

[0011] (2) Under nitrogen protection, 2,6-difluoro-4-bromoaniline intermediate I, diazotizing reagent and fluorinating reagent were added to the above reaction vessel in sequence. After stirring evenly, the mixture was raised to the set temperature. The mixture was kept at this temperature until the normalized content of 2,6-difluoro-4-bromoaniline intermediate I in the total material was <1% by liquid chromatography. After solvent removal, the product 3,4,5-trifluorobromobenzene was obtained by vacuum distillation.

[0012] In the above technical solution, in step (1), the molar ratio of 2,6-difluoroaniline to brominating reagent is 1:1-5, the molar ratio of the amount of organic solvent to 2,6-difluoroaniline is 1-10:1, and the molar ratio of 2,6-difluoroaniline to catalyst A is 1-20:1; in step (2), the molar ratio of 2,6-difluoro-4-bromoaniline intermediate I to diazotizing reagent is 1:1-5, and the molar ratio of 2,6-difluoro-4-bromoaniline intermediate I to fluorinating reagent is 1:1-5.

[0013] In the above technical solution, the set temperature in steps (1) and (2) is 0-120℃.

[0014] In the above technical solution, the organic solvent mentioned in step (1) is any one of the following: halogenated hydrocarbon solvent, aromatic solvent, ether solvent, ester solvent or alcohol solvent, or strong polar solvent containing heteroatoms.

[0015] In the above technical solution, the catalyst A mentioned in step (1) is any one or a mixture of two of the following: ferric chloride, copper chloride, iron powder, azobisisobutyronitrile, BPO, potassium carbonate, and sodium carbonate.

[0016] In the above technical solution, the brominating reagent mentioned in step (1) is any one or a mixture of two of NBS, Br2, NaBr+H2O2, and dibromohydantoin.

[0017] In the above technical solution, the diazotizing reagent mentioned in step (2) is any one or a mixture of two of sodium nitrite, nitrosyl sulfate, tert-butyl nitrite, and isopropyl nitrite.

[0018] In the above technical solution, the fluorinating agent mentioned in step (2) is any one or a mixture of two of KF, HF, HF+Et3N, tetrabutylammonium fluoride, and tetramethylammonium fluoride.

[0019] Preferably, the halogenated hydrocarbon solvent is dichloromethane, dichloroethane, etc., the aromatic solvent is toluene, xylene, etc., the ether solvent is tetrahydrofuran, etc., the ester solvent is methyl acetate, ethyl acetate, etc., the alcohol solvent is methanol, ethanol, etc., and the heteroatom-containing strongly polar solvent is DMF, acetonitrile, DMSO, etc.

[0020] In the above technical solution, the reaction temperature in steps (1) and (2) is preferably 30-60℃.

[0021] The method of this invention has multiple sources of raw materials with obvious cost advantages, the preparation method is safer and more convenient, the total yield is high and the amount of waste is small, which is conducive to industrialization. Detailed Implementation

[0022] The following describes in detail the specific embodiments of the technical solution of the present invention, but the present invention is not limited to the following description:

[0023] Example 1: Stepwise preparation of 3,4,5-trifluorobromobenzene

[0024]

[0025] Small-scale stepwise preparation of the target product:

[0026] (1) 12.9 g (0.10 mol) of 2,6-difluoroaniline, 30 mL of dichloroethane, 21.3 g (0.12 mol) of NBS, and 0.3 g of azobisisobutyronitrile catalyst were added to a 500 mL reactor. The mixture was heated to 40 degrees and stirred for 12 h. The byproduct succinimide was removed by filtration. Dichloroethane was recovered under reduced pressure with a recovery rate of 90%. 18.6 g of intermediate I with a purity greater than 98% was obtained by vacuum distillation with a yield of 90%.

[0027] (2) In another 500mL reactor, 20.7g (0.10mol) of intermediate I, 30mL of acetonitrile, 16g (0.1mol) of triethylamine hydrofluoric acid salt, and 12.4g (0.12mol) of tert-butyl nitrite were added dropwise. The mixture was heated to 40 degrees and stirred for 4h. After the reaction was deemed qualified, the acetonitrile was recovered under reduced pressure. Then, acid water was added to adjust the pH to 2. Ethyl acetate was added for extraction, separation, and solvent removal to recover ethyl acetate (which was directly reused in the next batch of reaction). The recovery rate was 92%. 17.3g of 3,4,5-trifluorobromobenzene with >96% purity was obtained by vacuum distillation, with a yield of 83%.

[0028] Example 2: Optimization of different conditions for the synthesis of 3,4,5-trifluorobromobenzene

[0029]

[0030] The pilot program is similar to the implementation plan in Column 1, as detailed in the list:

[0031]

[0032] Example 3: One-pot preparation of 3,4,5-trifluorobromobenzene

[0033]

[0034] Small-scale one-pot method for preparing the target product:

[0035] (1) 12.9 g (0.10 mol) of 2,6-difluoroaniline, 30 mL of acetonitrile, 21.3 g (0.12 mol) of NBS and 0.3 g of azobisisobutyronitrile catalyst were added to a 500 mL reactor. The mixture was heated to 40 degrees and stirred for 10 h. After the reaction was deemed acceptable, the mixture was cooled and 16 g (0.1 mol) of triethylamine hydrofluoric acid salt was added. 12.4 g (0.12 mol) of tert-butyl nitrite was added dropwise. The mixture was heated to 40 degrees and stirred for 4 h. After the reaction was deemed acceptable, acetonitrile was recovered under reduced pressure. Acid water was added to adjust the pH to 2. Ethyl acetate was added for extraction, separation, and solvent removal to recover ethyl acetate (which was directly reused in the next batch of reaction). The recovery rate was 93%. 14.7 g of 3,4,5-trifluorobromobenzene with >96% purity was obtained by vacuum distillation. The total yield was 70%.

[0036] Example 4: One-pot preparation of 3,4,5-trifluorobromobenzene

[0037]

[0038] One-pot method for preparing the target product at the kilogram level:

[0039] (1) 2.58 kg (20 mol) of 2,6-difluoroaniline, 6 L of acetonitrile, 4.26 kg (24 mol) of NBS and 50 g of azobisisobutyronitrile catalyst were added to a 20 L reactor. The mixture was heated to 40 degrees and stirred for 10 h. After the reaction was deemed acceptable, the mixture was cooled and 3.2 kg (20 mol) of triethylamine hydrofluoric acid was added. 2.48 kg (24 mol) of tert-butyl nitrite was added dropwise. The mixture was heated to 40 degrees and stirred for 4 h. After the reaction was deemed acceptable, acetonitrile was recovered under reduced pressure. Acid water was added to adjust the pH to 2. 6 L of ethyl acetate was added for extraction, separation, and solvent removal to recover the ethyl acetate (which was directly reused in the next batch of reaction). The recovery rate was 95%. 3 kg of 3,4,5-trifluorobromobenzene with >96% purity was obtained by vacuum distillation. The total yield was 71.4%.

[0040] The above examples are merely illustrative of the technical concept and features of the present invention and should not be construed as limiting the scope of protection of the present invention. All equivalent transformations or modifications made in accordance with the essence of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing 3,4,5-trifluorobromobenzene, characterized in that, Includes the following steps: (1) 2,6-difluoroaniline, brominating reagent, and catalyst A are added to an organic solvent at a certain temperature to carry out a bromination reaction to obtain product 2,6-difluoro-4-bromoaniline intermediate I; (2) In an organic solvent, 2,6-difluoro-4-bromoaniline intermediate I, diazotizing agent, and fluorinating agent are added at a certain temperature and reacted in a one-pot manner to obtain the product 3,4,5-trifluorobromobenzene. The reaction formula is: ； The brominating reagent is NaBr + H2O2; The catalyst A is ferric chloride; The diazotizing agent is isopropyl nitrite; The fluorinating agent is HF; In step (1), the molar ratio of 2,6-difluoroaniline to the brominating reagent is 1:1-5, the molar ratio of the organic solvent to 2,6-difluoroaniline is 1-10:1, and the molar ratio of 2,6-difluoroaniline to catalyst A is 1-20:1; in step (2), the molar ratio of 2,6-difluoro-4-bromoaniline intermediate I to the diazotizing reagent is 1:1-5, and the molar ratio of 2,6-difluoro-4-bromoaniline intermediate I to the fluorinating reagent is 1:1-5. The reaction temperatures in steps (1) and (2) are 30-60℃ respectively.

2. The method according to claim 1, characterized in that, Includes the following steps: (1) Under nitrogen protection, organic solvent, 2,6-difluoroaniline, brominating reagent and catalyst A are added to the reaction vessel in sequence. After stirring evenly, the mixture is raised to the set temperature. The mixture is kept at this temperature until the normalized content of 2,6-difluoroaniline in the total material is <1% by liquid chromatography. 2,6-difluoro-4-bromoaniline intermediate I solution is obtained. (2) Under nitrogen protection, 2,6-difluoro-4-bromoaniline intermediate I, diazotizing reagent, and fluorinating reagent were added sequentially to the reaction vessel. After stirring evenly, the mixture was raised to the set temperature. The mixture was kept at this temperature until the normalized content of 2,6-difluoro-4-bromoaniline intermediate I in the total material was <1% by liquid chromatography. After solvent removal, the product 3,4,5-trifluorobromobenzene was obtained by vacuum distillation.

3. The method according to claim 2, characterized in that, The organic solvent mentioned in step (1) is any one of the following: haloalkanes, aromatics, ethers, esters or alcohols, or strongly polar solvents containing heteroatoms; The strongly polar solvent containing heteroatoms is DMF, acetonitrile, or DMSO.

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