Background and overview[1]
5-Fluoro-2-methylphenylmagnesium bromide can be used as a pharmaceutical synthesis intermediate.
Preparation[1]
Generation of Grignard reagent 5-fluoro-2-methylphenylmagnesium bromide in a single CSTR: Activate a slurry of magnesium (227g, 9.4mol) in MeTHF (1L) to prepare 1.0MINT1 Grignard reagent (1207g) , occurs immediately after activating stirring. To compound 1 (23% (w/w)), MeTHF was added to the CSTR at a rate of 34.5 mL/min with a steady state τ of 0.5 h and a vessel temperature of 40 °C. The reaction solution exits via a dip tube and is used to isolate the solid magnesium in the CSTR, and the solution is then collected in an accumulation vessel at a 1x rate (34.5 mL/min). The operation ran as a start/stop operation over 5 days, with a total processing time of 32 hours. Pause overnight. The yield of 5-fluoro-2-methylphenylmagnesium bromide was 1.68 kg (69.6 mol). In total, there were 30 liters of 5-fluoro-2-methylphenylmagnesium bromide Grignard reagent (97% conversion, 95% yield).
Application
5-Fluoro-2-methylphenylmagnesium bromide can undergo the following reactions:
Continuously pump 5-fluoro-2-methylphenylmagnesium bromide Grignard reagent (1.02M) at 11.67mL/min simultaneously into 10% (w/w) DMF in THF, 11.67mL/ min. Add 4MLiBH4, continuously pump the solution in THF into CSTR2 at 1.56mL/min, operate at 22°C for 0.5 hours, add 25% (w/w) methanol and H2SO4, the concentration is 15.1mL/min. Add toluene, combine several layers, wash with NaHCO3 aqueous solution, and concentrate to oil (3.93kg, yield 82.4%). Cyclohexane (1400mL) was added, the mixture was filtered, the wet filter cake was washed with cyclohexane (1000mL), and the solid was dried at 22°C for 17 hours to obtain 555g of compound 2 (recovery rate 95.4%, total yield 50%) 78%) is a white powder with a purity of 99.9%.
Main reference materials
[1] FlowGrignardandLithiation: Screening Tools and Development of Continuous Processes for a BenzylAlcoholStartingMaterial
微信扫一扫打赏
Chinese