Preparation of 5-bromo-2-fluorotrifluorotoluene (alias 2-bromo-5-fluorotrifluorotoluene)_Kain Industrial Additive

Background and overview^[1][2]

2-Bromo-5-fluorotrifluorotoluene is a widely used pharmaceutical intermediate. At present, the market demand for 2-bromo-5-fluorotrifluorotoluene as an intermediate is gradually increasing. The synthesis of 2-bromo-5-fluorotrifluorotoluene in the currently published literature and patents mainly uses m-trifluoromethylfluorobenzene as the starting material, and is directly brominated in the presence of acid and brominating agent to obtain 2- Bromine-5-fluorotrifluorotoluene (herein referred to as m-trifluoromethylfluorobenzene direct bromination method, the bromination agent includes copper bromide, hydrogen bromide, N-bromosuccinimide (NBS), bromine dimethyl bromide (DMBS), dibromohydantoin, sodium bromide, potassium bromide, bromine chloride, 1,3-dibromo-2,4-imidazoledione, or combinations thereof; acids include concentrated Sulfuric acid, glacial acetic acid. The brominating agent used in the direct bromination of m-trifluoromethylfluorobenzene is expensive and the reaction cost is high. Dalian Jiuxin Biochemical has developed an indirect bromination method, which uses m-trifluoromethylfluorobenzene. Benzene is used as the starting material, and is first nitrated, then reduced, then diazotized, and finally brominated with hydrobromic acid to synthesize 2-bromo-5-fluorotrifluorotoluene. m-Trifluoromethylfluorobenzene indirect bromination method There are many reaction steps and the operation is complex. Compared with the direct bromination method, the reaction cost is still not reduced. Whether it is the direct bromination method or the indirect bromination method, m-trifluoromethylfluorobenzene is used as the raw material, and m-trifluoromethyl fluorobenzene is used as the raw material. Fluorobenzene is expensive and the cost is high. Literature reports that there are two main routes to synthesize m-trifluoromethylfluorobenzene: one is to use m-trifluoromethylaniline with HF-pyridine (HF mole fraction is 0.86) and sodium nitrite. Diazotization (the reaction temperature needs to be lowered to below -30°C) and then heating and cracking to obtain m-trifluoromethylfluorobenzene. The second method is to use m-nitrotrifluorotoluene under the catalysis of Ph4PBr - NO2 is fluorinated by KF to obtain m-trifluoromethyl fluorobenzene. Although the m-trifluoromethylaniline raw material used in method one is cheap, the reaction temperature needs to be lowered to below -30°C, which has the disadvantages of high equipment requirements and high energy consumption in industrial production. The catalyst used in method two is expensive , the yield is low, only 53%, and the reaction cost is high. Therefore, it is necessary to find a 2-bromo-5-fluorine with cheap and easily available raw materials, mild reaction conditions, short steps, high yield, low cost, and suitable for industrial production. The preparation method of benzene trifluoride is a technical problem that needs to be solved urgently.

Apply^[2]

2-Bromo-5-fluorotrifluorotoluene is a widely used pharmaceutical intermediate. It can be used to synthesize 2-trifluoromethyl-4-aminobenzonitrile, and 2-trifluoromethyl-4-aminobenzonitrile. -Aminobenzonitrile is a raw material and intermediate used in the synthesis of the anti-tumor drug bicalutamide. Bicalutamide is an anti-androgenic, non-corticosteroid that is well tolerated and has no significant side effects. Examples of its application are as follows: synthesis of 2-trifluoromethyl-4-aminobenzonitrile, which includes the following steps: (a) providing m-trifluoromethylfluorobenzene; (b) the m-trifluoromethylfluorobenzene in A bromination reaction occurs in the presence of an acid and a brominating agent to obtain 2-bromo-5-fluoro-trifluorotoluene; (c) the 2-bromo-5-fluoro-trifluorotoluene undergoes Grignard reaction to prepare Grignard Reagent, a formylation reaction occurs in the presence of a formylation reagent to obtain 2-trifluoromethyl-4-fluorobenzaldehyde; (d) the 2-trifluoromethyl-4-fluorobenzaldehyde undergoes a cyanation reaction , obtain 2-trifluoromethyl-4-fluorobenzonitrile; (e) react the 2-trifluoromethyl-4-fluorobenzonitrile with an ammoniating reagent to obtain 2-trifluoromethyl-4-amino Benzonitrile.

Preparation^[1,3-4]

Method 1: A method for preparing 2-bromo-5-fluorotrifluorotoluene, which includes the following steps: carrying out a cleavage reaction of anhydrous compound 1 or compound 1' in an organic solvent under anhydrous conditions to prepare Obtain 2-bromo-5-fluorotrifluorotoluene. The reaction of attaching the amino protecting group to m-trifluoromethylaniline, the bromination reaction, and the reaction of removing the amino protecting group of m-trifluoromethylaniline described in the present invention can all be carried out in the same reaction kettle, and there is no need to transfer or store materials. The above preparation method has cheap and easily available raw materials, short reaction steps, mild reaction conditions, and high bromine utilization. The high positioning selectivity of bromine makes the final product have low isomer impurities, high reaction conversion rate, high yield, and product It has high purity, low production cost and is suitable for industrial production.

Method 2: A method for preparing 2-bromo-5-fluorotrifluorotoluene. The preparation method uses m-fluorotrifluorotoluene as raw material, under the conditions of concentrated sulfuric acid and composite catalyst, stir and dropwise add bromine After separation and purification, 2-bromo-5-fluorotrifluorotoluene is obtained:

The detailed preparation method is as follows:

1) Put the corresponding mass of concentrated sulfuric acid, composite catalyst and raw materials into the reaction vessel in sequence, maintain the reaction temperature at 20-50°C, and slowly add the corresponding mass of bromine under the regulation of stirring;

2) After the dropwise addition is completed, keep the reaction temperature at 20-55°C to continue the reaction, and use a gas chromatograph to monitor the raw material content when the content is less than 1.0%, stop the reaction;

3) Cool the product obtained in step 2) to room temperature and perform a standing separation operation to obtain the crude product;

4) Adjust the pH of the crude product obtained in step 3) in water. When pH=7, distill under reduced pressure to obtain the final product.

Method 3: A synthesis method of 2-bromo-5-fluorotrifluorotoluene. The synthesis method uses m-fluorotrifluorotoluene in a nitric acid/sulfuric acid system to obtain 5-fluoro-2-nitrotrifluorotoluene. Fluorotoluene is then reduced in a catalytic hydrogenation system of Raney nickel to obtain 5-fluoro-2-aminotrifluorotoluene, and finally undergoes diazotization and bromination of cuprous bromide, hydrobromic acid, and sodium nitrite. Using this method, the target compound 2-bromo-5-� was synthesized with high yield and high purity.��Trifluorotoluene. This synthesis method can obtain the product in three steps. The purity of the product is greater than 98%, and the yield is 76.1%. The raw materials are easily available, the catalyst can be recycled, and the reaction conditions are mild and easy to control. Includes the following steps:

1) Cool m-fluorotrifluorotoluene to below 10°C, add a mixture of nitric acid and concentrated sulfuric acid, and add it dropwise into the reaction kettle under vigorous stirring. The mole ratio of the mixture to m-fluorotrifluorotoluene The equivalent ratio is 1.1~1.5:1; during the dropping process, the temperature should not exceed 25°C. After the dropping is completed, react at room temperature for 2.5 hours. Cool, separate the organic layer, freeze, recrystallize with petroleum ether or n-hexane, filter after the freezing temperature is less than 10°C, and dry to obtain the intermediate 5-fluoro-2-nitrotrifluorotoluene;

2) Add 5-fluoro-2-nitrotrifluorotoluene, Raney nickel or palladium carbon catalyst, and ethanol into the autoclave, keep the temperature at 30-35°C, and continuously fill with hydrogen to maintain 0.5MPa until no more suction to hydrogen. Filter, recover the catalyst, recover ethanol by distillation under reduced pressure, obtain an oil, distill under reduced pressure, and collect the intermediate 4-fluoro-2-trifluoromethylaniline in the fraction at 70-71°C/18mmHg;

3) Mix 4-fluoro-2-trifluoromethylaniline with hydrobromic acid with a mass concentration of 40%, use a low-temperature bath to cool it to 5°C, add cuprous bromide; dissolve sodium nitrite in water, Under vigorous stirring conditions, add dropwise to the reaction kettle; after the dropwise addition, react at low temperature for 30 minutes, and then react at room temperature for 1 to 2 hours. Stop the reaction when there are no bubbles; pour into a separatory funnel and separate the organic layer and product layer. The pure product was obtained by distillation under reduced pressure, with a purity greater than 98% and a yield of 76.1%.