875446-55-2

96826-25-4

944317-92-4

Example 4: One-pot preparation of 1-bromo-4-fluoro-5-isopropyl-2-methoxybenzene (BrMIP); To a 2L round bottom flask equipped with a magnetic stirrer, an argon inlet, and a temperature probe was added a commercially available 3M methylmagnesium chloride (MeMgCl) solution in THF (600 mL, 1.80 mol). The solution was cooled to -10°C and a solution of acetophenone FMAP (170 g, 1.01 mol) in anhydrous dichloromethane (DCM, 800 mL) was added slowly and dropwise, keeping the internal temperature below 0°C. The reaction mixture was stirred at 0 °C for 2 hours. The reaction was quenched slowly with a 2M aqueous hydrochloric acid solution (900 mL), controlling the internal temperature to be below 20 °C (note: the reaction is significantly exothermic). The quenched reaction mixture was stirred at 20 °C for 1 h. The organic and aqueous phases were subsequently separated. The organic phase was washed sequentially with water (1000 mL) and brine (800 mL), and concentrated under reduced pressure to 220 g. The concentrate contained FMOL and MIPEN in a ratio of 5:6, and the total amount of material was estimated to be 0.97 mol by 1H NMR. Nuclear magnetic resonance (NMR) and high performance liquid chromatography (HPLC) analyses showed the product was essentially free of raw material FMAP, and the product identification The standard was referred to Example 2. A portion of the above concentrate (94 mL, ~73 g FMOL/MIPEN, ~0.42 mol) was diluted with methanol (MeOH), purged with nitrogen (N2) and then 5% palladium carbon (Pd-C, 1.70 g, 0.2 mol%) was added. The mixture was purged with hydrogen (H2) and reacted at 50 °C and 3 bar pressure until HPLC analysis showed that the reaction was complete. The catalyst was removed by filtration through diatomaceous earth (Celite). The filtrate was transferred to a new flask and 1,3-dibromo-5,5-dimethyl-acetonitrile (60.7 g, 208 mmol) was added in batches, controlling the temperature to be below 40 °C (note: the reaction is exothermic). After the addition was completed, the reaction was continued with stirring for 8 h. HPLC monitored the completion of the reaction. The reaction was quenched with sodium bisulfite (NaHSO3, 5.0 g) and stirring was continued for 15 minutes. The solution was concentrated to 1/5 of the original volume and diluted with water (500 mL). The resulting mixture was extracted with petroleum ether (300 mL) and the organic phase was washed sequentially with water (500 mL), 1M aqueous sodium hydroxide (250 mL), water (500 mL) and brine (200 mL). The organic phase was dried over anhydrous sodium sulfate (Na2SO4), filtered and the solvent was removed under reduced pressure to give BrMIP as a light yellow oil (93.03 g, 91% yield as FMAP).1H NMR (CDCl3) δ 1.22 (d, J=6.9 Hz, 6H, 2*Me), 3.14 (sep, J=6.9 Hz, 1H), 3.85 (s 3H), 6.60 (d, J=11.8 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H). The product BrMIP was essentially free of the demethylated impurity BrMET by HPLC and NMR analysis, and the identification criteria were referred to Example 2.