52189-63-6

850793-25-8

Example 50: Synthesis of 3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-2-chloro-3-fluorophenoxy}-5-chlorobenzenecarbonitrile; Step 1: Preparation of 3-fluoro-5-methoxyphenol (50-1); Under nitrogen protection, 1-fluoro-3,5-dimethoxybenzene (25 g, 160 mmol) was dissolved in dichloromethane ( 200 mL, 0.8 M) and subsequently cooled to -15 °C. Boron tribromide (176 mL, 176 mmol, 1 M solution in dichloromethane) was added slowly. The reaction mixture was stirred at -15 °C for 1.5 h, followed by stirring at room temperature for 10 min. The reaction mixture was cooled again to 0 °C and the reaction was quenched by slowly adding water (150 mL). The aqueous layer was extracted with dichloromethane (3 x 100 mL). The organic layers were combined, dried over sodium sulfate and concentrated. Purification by silica gel column chromatography (1%-30% ethyl acetate/hexane) afforded the mono-demethylated product 3-fluoro-5-methoxyphenol (50-1) (15 g, 67% yield).