Application of 4-bromo-3-chlorobenzoic acid_Kain Industrial Additive

Background and overview^[1][2]

4-Bromo-3-chlorobenzoic acid can be used as a pharmaceutical and chemical synthesis intermediate. If 4-bromo-3-chlorobenzoic acid is inhaled, move the patient to fresh air; if there is skin contact, take off contaminated clothing, rinse the skin thoroughly with soap and water, and seek medical attention if you feel unwell; if the eyes If exposed to sunlight, separate eyelids, rinse with running water or saline, and seek medical attention immediately; if ingested, rinse mouth immediately, do not induce vomiting, and seek medical attention immediately.

Apply^[2]

4-Bromo-3-chlorobenzoic acid can be used as a pharmaceutical and chemical synthesis intermediate. For example, the following compounds can be synthesized:

To a stirred solution of 4-bromo-3-chlorobenzoic acid (5.0g, 21.2mmol) in dichloromethane (50ml), add N-methoxymethylamine (1.43g, 23.34mmol), 1-ethyl hydroxy-3-(3-dimethylaminopropyl)carbodiimide (4.16g, 25.48mmol), 7-aza-1-hydroxybenzotriazole (590mg, 4.25mmol) and N-ethylbis Isopropylamine (7.42ml, 42.5mmol). The mixture was then allowed to react at room temperature overnight. Add 100ml ethyl acetate and 100ml water. The organic phase was washed once with saturated sodium bicarbonate solution (50 ml). The organic phase was then concentrated under reduced pressure. The crude product was purified by flash chromatography to obtain 5.91 g of 4-bromo-3-chloro-N-methoxy-N-methyl-benzamide.

Preparation^[3]

The preparation process of 4-bromo-3-chlorobenzoic acid is as follows:

Step 1: Heat a solution of 4-aminobenzoic acid methyl ester (15g provided by Aldrich) in acetonitrile to 0° with stirring. N-Chlorosuccinimide (14.6 g) was added in one portion and the reaction mixture was refluxed with stirring for 4 hours. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was dissolved in dichloromethane and the extract was washed with cold 1M aqueous sodium hydroxide solution. The methylene chloride solution was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. Methyl 4-amino-3-chlorobenzoate (17.1 g) (Synthesis 1985, 669-670) was obtained as a crystalline solid and was used without further purification.

Step 2): A solution of methyl 4-amino-3-chlorobenzoate (17.0g) in 48% hydrobromic acid (200ml) was stirred at 0°. Sodium nitrite solution (6.3 g in 25 ml water) was added dropwise over 45 minutes and the reaction mixture was maintained at 0-5 °C. The mixture was stirred at 0-5° for 2 hours. A solution of sodium metabisulfite (5.5g) and sodium hydroxide (3.6g) in water (40ml) was added to copper (II) sulfate pentahydrate (25.5g) and sodium bromide (12.3g) in water. of hot solution (80). ml). The stirred suspension was maintained at 75° and cold diazonium salt solution was added. The mixture was stirred for 15 minutes and 48% hydrobromic acid (30 ml) was added. The mixture was cooled to room temperature and extracted with diethyl ether. The ether extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solution was evaporated in vacuo. Methyl 4-bromo-3-chlorobenzoate (20.4 g) was obtained as a crystalline solid and was used without further purification.

Step 3) Reflux 4-bromo-3-chlorobenzoic acid methyl ester (20g) in aqueous sodium hydroxide solution (60ml, 10% solution) with stirring for 2 hours. The resulting solution was cooled, diluted with water and acidified with concentrated hydrochloric acid solution. The aqueous mixture was extracted with diethyl ether, and the ether extract was dried over anhydrous magnesium sulfate. Solvent was removed in vacuo. 4-Bromo-3-chlorobenzoic acid (18 g) was obtained as an off-white solid and was used without further purification.

Main reference materials

[1] WO2013144224.ACETYLENIC MICROBIOCIDES

[2] EP0279698) .PESTICIDAL COMPOUNDS