137347-01-4

89943-11-3

1. 2-Bromo-3-hydroxypyridine (11.95 mmol), ethyl iodide (23.91 mmol) and K2CO3 (21.51 mmol) were dissolved in DMF (20 mL) and heated to 80 °C for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure and the residue was diluted with H2O (20 mL) and extracted with EtOAc (3 x 25 mL). The organic phases were combined, washed sequentially with H2O (25 mL) and brine (25 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to give 2-bromo-3-ethoxypyridine as an off-white solid (1.99 g, 83% yield). 2. 2-bromo-3-ethoxypyridine (0.01 mol) was slowly added to a mixture of fuming nitric acid (8 mL) and concentrated sulfuric acid (8 mL) at 0°C. The reaction solution became clear yellow. After the reaction solution turned to a clear yellow color, it was heated to 55°C for 1 hour. Cooled to room temperature, the reaction solution was slowly added dropwise to ice water (400 mL). The solid was collected by filtration to give 2-bromo-3-ethoxy-6-nitropyridine as a light yellow solid (1.40 g, 57% yield). 3. 2-Bromo-3-ethoxy-6-nitropyridine was dissolved in a minimal amount of EtOAc (10 mL) and diluted with EtOH (55 mL). 10% Pd/C catalyst (made as a slurry with EtOAc) was added and the mixture was placed in a Parr apparatus and reacted under hydrogen atmosphere (40 psi down to 18 psi) for 1 hour. Upon completion of the reaction, the catalyst was removed by filtration with diatomaceous earth and the filtrate was concentrated. The residue was diluted with 6 M HCl (50 mL) and extracted with EtOAc (3 x 50 mL) and the organic phase was discarded. The aqueous phase was alkalized with 1 M NaOH (50 mL) and extracted with EtOAc (3 x 50 mL). The organic phases were combined, dried over anhydrous MgSO4 and concentrated under reduced pressure to give 5-ethoxypyridin-2-amine as a brown oil (722 mg, 94% yield). 4. Example 307 was prepared in 40% yield with non-critical modifications according to Method C. HRMS (ESI) calculated value C11H10F3N5O2S + H 335.0585, measured value 335.0584.