Thionyl Chloride → 2-(1-Chloro-2-methylpropyl)-5-fluoro-3-methyl-1-benzofuran

Participants

Reaction Steps

To a solution of 1-(5-fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-ol (1.128 g) obtained in Example A192(2) in tetrahydrofuran (10 mL) was added thionyl chloride (0.45 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give a crude 2-(1-chloro-2-methylpropyl)-5-fluoro-3-methyl-1-benzofuran (1.10 g). To the obtained 2-(1-chloro-2-methylpropyl)-5-fluoro-3-methyl-1-benzofuran (485 mg) were added ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (500 mg) obtained in Example 1(2), sodium iodide (599 mg), sodium carbonate (424 mg) and N,N-dimethylformamide (5 mL) and the mixture was stirred at 80° C. for 13 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-50:50, v/v) to give a colorless amorphous compound (123 mg). The obtained amorphous compound (123 mg) was dissolved in ethanol (2.0 mL) and tetrahydrofuran (2.0 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, water (4 mL) was added to the residue, and the mixture was neutralized with 1N hydrochloric acid (1.0 mL) under ice-cooling and the mixture was stirred for 20 min. The resulting precipitate was collected by filtration, and dried to give the title compound (97 mg, 11%) as a yellow amorphous compound.

Provenance & Evidence