Synthesis
2-Chloro-5-fluoro-3-methoxypyridine (D47, 0.11 g, 0.70 mmol) was used as starting material and dissolved in anhydrous toluene (3 ml). Sodium tert-butoxide (0.094 g, 0.98 mmol), Pd2(dba)3 (0.064 g, 0.07 mmol), BINAP (0.131 g, 0.21 mmol) and benzophenone imine (0.14 ml, 0.84 mmol) were added sequentially. The reaction mixture was degassed (three evacuation/nitrogen filling cycles) and subsequently heated to 80 °C and stirred for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, diluted with ether (80 ml) and filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure and the resulting oil was dissolved in tetrahydrofuran (8 ml) and 2M aqueous hydrochloric acid (0.35 ml, 0.70 mmol) was added. After stirring for 1.5 h at room temperature, the reaction solution was neutralized with saturated aqueous sodium bicarbonate and diluted with dichloromethane (40 ml). The organic phase was separated and the aqueous phase was back-extracted with dichloromethane (2 x 10 ml). The organic layers were combined, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by rapid chromatography on silica gel (Biotage SP4 12M, cyclohexane/ethyl acetate 60/40) to afford 5-fluoro-3-methoxypyridin-2-amine (D48, 0.071 g, 0.49 mmol, 70% yield) as a yellow solid.UPLC analysis: retention time 0.28 min, mass spectrum peak observed was 143 (M+1). The calculated mass of the molecular formula C6H7FN2O is 142.
