4-Chlorophenethyl bromide 97

Chemical Properties

Pale yellow oil

Uses

4-Chlorophenethyl Bromide is used as a reagent in the synthesis of terfenadine-based analogs as potential antibacterials. 4-Chlorophenethyl Bromide is also used in the preparation of tertiary amine and indole derivatives as potent retinoid-related orphan receptor gamma-t (RORγt) inverse agonists.

Synthesis

General procedure for the synthesis of 1-(2-bromoethyl)-4-chlorobenzene from 4-chlorophenyl ethanol: volumetric efficiency of 1.76 liters per kilogram of 2-(4'-chlorophenyl)ethanol feedstock or 758 grams of 2-(4'-chlorophenyl)ethyl bromide product per liter (assay corrected). PROCESS DESCRIPTION: Use a reactor with fixed vents and a caustic scrubber to capture any HBr gas that may be produced during the reaction. Add 2-(4'-chlorophenyl)ethanol (1.00 Kg, 6.39 mol, 1.00 eq.) to the reactor. The reactor contents were cooled to 0°C. The feed pump and lines were flushed with cyclohexane (0.019 Kg) and the flushing solution was introduced to waste disposal. Phosphorus tribromide (0.869 Kg, 3.21 moles, 0.503 eq.) was added to the cooled solution while the stirred reactor contents were maintained at 0-10°C. The reaction was highly exothermic and the reaction temperature was controlled by the rate of addition of jacket temperature. The feed pump and lines were again flushed with cyclohexane (0.019 Kg) and the flushing solution was introduced to waste disposal. The resulting reaction mixture was heated to 25°C (20°C to 30°C) and stirring was continued at this temperature for 2 hours (1 to 3 hours). The reaction mixture was then slowly heated to 80°C (75 to 85°C) over 60 minutes (45 to 75 minutes) and stirring was continued at this temperature for 3 hours (2 to 4 hours). A slightly cloudy emulsion is formed during heating. The reactor contents were cooled to 22 °C and then a sample of the reaction mixture was analyzed by HPLC for completion of the reaction (HPLC peak area > 99%). The reaction mixture was a thick but easily stirred emulsion. The caustic washer contents were discharged into a receiver containing purified water (0.514 Kg). Cool the receiver contents to 5-20°C. Transfer the reaction mixture from the reactor to the receiver at a rate slow enough to maintain the temperature of the stirred receiver contents at about 15°C. The receiver contents were heated to 35-40°C and filtered through a polishing filter. The reactor was washed with additional purified water (0.085 Kg) and the wash solution was passed through the filter into the aqueous product mixture. The phases were allowed to separate at 35-40°C. The lower phase was expelled from the upper phase. The lower phase weighed about 1.39 Kg and was about 96% pure 2-(4'-chlorophenyl)ethyl bromide, thus obtained in about 94.9% yield (assay corrected).

References

[1] Patent: US2009/143576, 2009, A1. Location in patent: Page/Page column 2; 9-10
[2] Patent: CN106478506, 2017, A. Location in patent: Paragraph 0122; 0123
[3] Patent: US5397793, 1995, A
[4] Patent: US2002/19531, 2002, A1
[5] Journal of the American Chemical Society, 1957, vol. 79, p. 3712,3715