preparation of 2-bromo-1-chloro-4-trifluoromethoxybenzene_kain industrial additive

background and overview^[1-2]

2-bromo-1-chloro-4-trifluoromethoxybenzene is a pharmaceutical intermediate, which can be prepared from 2-bromo-4-(trifluoromethoxy)aniline after diazotization and chlorination. 2-bromo-1-chloro-4-trifluoromethoxybenzene can be used to prepare triazolecarboxylic acid derivatives (such as 4-((4′-chloro-3′-(trifluoromethoxy)-[1, 1,-biphenyl]-4-yl)thio)-1h-1,1,2,3-triazole-5-carboxylic acid), these derivatives can be used as glycolate oxidase inhibitors.

preparation^[1-2]

report 1,

a solution of sodium nitrite (0.81g, 11.72mmol) in water (2ml) was added dropwise to 2-bromo-4-(trifluoromethoxy)aniline (1.18ml, 7.81mmol) at 5°c. in 6n hydrochloric acid solution. the mixture was stirred at this temperature for 40 minutes and then a solution of cucl (1.55 g, 15.62 mmol) in concentrated hcl (3 ml) was added dropwise. the mixture was allowed to warm to room temperature and stirred for 2-6 hours. dcm and water were added and the product was extracted twice. the combined organic layers were dried, filtered and concentrated. the crude compound was purified by flash column chromatography (20 g silica gel, heptane:acoet from 100:0 to 85:15) to give 2-bromo-1-chloro-4-trifluoromethoxybenzene (1.47 g, 68%).

report 2,

combine isopentyl nitrite (4 ml, 30 mmol), copper(ii) chloride (3.22 g, 24 mmol) and 4-bromo-2-(trifluoromethoxy)aniline (5.1 g, 20 mmol) in acetonitrile (80 ml) was heated at 70°c for 3 hours. the mixture was poured into aqueous hcl solution (0.5m, 50ml) and extracted with ethyl acetate (50ml×2). the combined extracts were washed with water (50 ml × 4) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. the residue was purified by silica gel flash column chromatography (petroleum ether) to obtain compound 2-bromo-1-chloro-4-trifluoromethoxybenzene.

main reference materials

[1] rombouts f j r , tresadern g , buijnsters p , et al. pyrido[4,3- e ][1,2,4]triazolo[4,3- a ]pyrazines as selective, brain penetrant phosphodiesterase 2 ( pde2) inhibitors[j]. acs medicinal chemistry letters, 2015, 6(3):150115135115001.

[2]from pct int. appl., 2019133770, 04 jul 2019