2-Bromo-4-chloro-6-fluorobenzaldehyde

Intermediate 10; 3-(2-Bromo-4-chloro-6-fluoro-phenyl)-5-methyl-[1, 2, 4]oxadiazole Step A: 2-Bromo-4-chloro-6-fluoro-benzaldehyde To a solution of 1, 2-dibromo-5-chloro-3-fluoro-benzene (10 g, 34.68 mmol) in heptane (27 ml) was added THF (44 ml) and the mixture was cooled to -45° C. Then iPrMgCl (38.14 ml, 38.14 mmol, 1M solution in THF) was added dropwise to the reaction mixture maintaining the temperature between -40° C. to -45° C. The mixture was stirred for 30 minutes at -40° C. before DMF (13.4 ml, 173.4 mmol) was added dropwise to the reaction mixture maintaining the temperature between -45° C. to -20° C. After stirring for another 15 minutes at -20° C., the reaction mixture was poured into a mixture of 2N HCl (20 ml) and ether (50 ml) at 0° C. The organic layer was separated and the aqueous layer was extracted two times with ether. The combined organic layers were dried with NaStep A: 2-Bromo-4-chloro-6-fluoro-benzaldehydeTo a solution of l, 2-dibromo-5-chloro-3-fluoro-benzene (10 g, 34.68 mmol) in heptane (27 ml) was added THF (44 ml) and the mixture was cooled to -45°C. Then iPrMgCl (38.14 ml, 38.14 mmol, 1M solution in THF) was added dropwise to the reaction mixture maintaining the temperature between -40°C to -45°C. The mixture was stirred for 30 minutes at -40°C before DMF (13.4 ml, 173.4 mmol) was added dropwise to the reaction mixture maintaining the temperature between -45 °C to -20°C. After stirring for another 15 minutes at -20°C, the reaction mixture was poured into a mixture of 2N HC1 (20 ml) and ether (50 ml) at 0°C. The organic layer was separated and the aqueous layer was extracted two times with ether. The combined organic layers were dried with Na[A] Step 1: Slowly add isopropyl to a mixture of 1, 2-dibromo-5-chloro-3-fluorobenzene (5 g, 17.5 mmol) in n-hexane (12 mL) and tetrahydrofuran (20 mL) at -45°C. A solution of magnesium chloride in tetrahydrofuran (19.2 mol, 1 M) was maintained at a temperature of -40°C. DMF (6.4 g, 87.5 mmol) was then slowly added dropwise to the above reaction mixture and stirred for 30 minutes. The reaction system was prepared with hydrochloric acid (15 mL, 2.0M) Quenching.The mixture was warmed to room temperature and diluted with ethyl acetate (80 mL) and the organic phase was separated.The organic phase was washed with saturated brine, filtered, and the filtrate was concentrated under reduced pressure.The residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 10/1) to give 2-bromo-4-chloro-6-fluorobenzaldehyde (3 g, yield: 73percent) as a yellow solid.ΓΑ1 2-Bromo-4-chloro-6-fluoro-benzaldehydeTo a solution of l, 2-dibromo-5-chloro-3-fluoro-benzene (10 g, 34.68 mmol) in heptane (27 ml) was added THF (44 ml) and the mixture was cooled to -45 °C. Then, iPrMgCl (38.14 ml, 38.14 mmol, 1M solution in THF) was added dropwise to the reaction mixture maintaining the temperature between -40 °C to -45° C. The mixture was stirred for 30 minutes at -40 °C before DMF (13.4 ml, 173.4 mmol) was added dropwise to the reaction mixture maintaining the temperature between -45 °C to -20 °C. After stirring for another 15 minutes at -20 °C, it was poured into a mixture of 2N HC1 (20 ml) and ether (50 ml) at 0 °C. The organic layer was separated and the aqueous layer was extracted two times with ether. The combined organic layers were dried with NaStep 2: To a solution of GammaAlpha1 2-Bromo-4-chloro-6-fluoro-benzaldehydeTo a solution of l, 2-dibromo-5-chloro-3-fluoro-benzene (10 g, 34.68 mmol) in heptane (27 ml) was added THF (44 ml) and the mixture was cooled to -45 C. Then, iPrMgCl (38.14 ml, 38.14 mmol, 1M solution in THF) was added dropwise to the reaction mixture maintaining the temperature between -40 C to -45 C. The mixture was stirred for 30 minutes at -40 C before DMF (13.4 ml, 173.4 mmol) was added dropwise to the reaction mixture maintaining the temperature between -45 C to -20 C. After stirring for another 15 minutes at -20 C, it was poured into a mixture of 2N HC1 (20 ml) and ether (50 ml) at 0 C. The organic layer was separated and the aqueous layer was extracted two times with ether. The combined organic layers were dried with Na2S04 and evaporated in vacuo to obtain the title compound (7.8 g, 95%) as yellow solid.