1-Bromo-3-chloro-5-methoxybenzene is prepared by the reaction of 1-bromo-3-chloro-5-fluoro-benzene and Sodium methanolate. The specific synthesis steps are as follows:
A solution of 1-bromo-3-chloro-5-fluoro-benzene (42a, 55 g, 263 mmol) was cooled to 0° C. and treated with a 25percent methanolic sodium methoxide solution (68 mL, 315 mmol) and heated to 40° C. for 3 h. The solution was cooled and partitioned between water (1 L) and a 1:1 mixture of hexane/diethyl ether (3.x.200 mL). The combined extracts were washed with brine (60 mL), dried (Na2SO4), filtered and the solvents evaporated in vacuo to afford 42b as an oil (57.3 g, 92percent pure, 238 mmol). The ether 42b (43 g, 173 mmol) was treated with glacial HOAc (150 mL) and 48percent aqueous HBr (100 mL) and heated to 120° C. After 40 h, the volatiles were removed while heated to 80° C. and then cooled to RT. The residue was partitioned between water (100 mL) and DCM (3.x.250 mL). The combined extracts were washed with H2O (50 mL), aqueous NaHCO3solution (2.x.50 mL), brine (50 mL), and (MgSO4). The solvents were removed to afford 23.3 g of 1-Bromo-3-chloro-5-methoxybenzene as a grey solid.
