methyl 3-(2-amino-4-fluoroanilino)-2-methylpropanoate

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 3-(2-amino-4-fluorophenylamino)-2-methylpropanoate (10.0 g, 44.2 mmol) in toluene (200 mL) was added titanium tetraisopropanolate (18.8 g, 66.3 mmol). The mixture was stirred at 90° C. for 15 hours. The resultant mixture was concentrated in vacuo, and dissolved in tetrahydrofuran (200 mL), filtered through celite, and washed with tetrahydrofuran (100 mL). The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to afford 8-fluoro-3-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one as a black solid (6.5 g, 76%). The resultant mixture was concentrated in vacuo dissolved in tetrahydrofuran (200 mL) filtered through celite washed with tetrahydrofuran (100 mL) The filtrate was concentrated in vacuo the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 3-(4-fluoro-2-nitrophenylamino)-2-methylpropanoate (14.0 g, 54.6 mmol) in ethanol (250 mL) were added zinc powder (14.2 g, 218 mmol) and saturated ammonium chloride (28.4 mL) at 0° C. Once addition was completed, the reaction mixture was stirred at reflux for 1 hour. Then the mixture was cooled to room temperature, filtered, and washed with ethanol (200 mL). The organic phase was concentrated in vacuo, dissolved in water (250 mL), and extracted with ethyl acetate (200 mL*3). The combined organic layers was separated, dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to afford methyl 3-(2-amino-4-fluorophenylamino)-2-methylpropanoate as a black solid (10.0 g, 81%). Once addition at reflux for 1 hour filtered washed with ethanol (200 mL) The organic phase was concentrated in vacuo dissolved in water (250 mL) extracted with ethyl acetate (200 mL*3) The combined organic layers was separated dried over anhydrous sodium sulfate concentrated to give a residue The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1)