3-AMINO-2-BROMO-6-METHOXYPYRIDINE

Dark red solid

PREPARATION XXXVII Hydrogen bromide (48percent solution in water, 3000mL, 1.61mol, 15vol) was charged to a 20000mL flask and cooled to 5-10A stirred mixture of 2-methoxy-5-aminopyridine (10 g, 0. 081 mol, 1. 0 equiv) and sodium acetate (6.6 g, 0. 081 mol, 1.0 equiv) in 60 ML of acetic acid was treated dropwise with bromine (12.9 g, 0.081 mol, 1.0 equiv). After 20 minutes, the reaction mixture was poured into 1000 mL of 10percent aqueous sodium hydroxide solution and extracted with three 250 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness. Chromatography on Si02 (20percent hexanes in dichloromethane) gave 5- AMINO-6-BROMO-2-METHOXYPYRIDINE (6.5 g, 40percent yield) as a purple solid.To a solution of 2-bromo-6-methoxy-3-nitro-pyridine (15.0 g, 64.37 mmol) in ethanol (100 mL) and water (100 mL) was added iron (18.0 g, 321.86 mmol) and ammonium chloride (17.2 g, 321.86 mmol) under N2 atmosphere. After addition, the mixture was stuffed at 60 Cfor 5 h and then filtered. The filtrate was diluted with water (200 mL) and extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give 2-bromo-6-methoxy-pyridin-3-amine(12.0 g, 92%) as a yellow oil. 'H NMR (400 MHz, CDC13) oe 7.04 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H), 3.86 (s, 3H), 3.72 (br. s, 2H).A mixture of 3-amino-2-bromo-6-methoxy pyridine (4.0 g, 19.7 mmol), tert-butyl 3-butenoate (8.4 g, 59.1 mmol), sodium bicarbonate (5.0 g, 59.1 mmol) dicyclohexyl- [2-(2, 4, 6-triisopropyl-3-phenyl-phenyl)phenyl]phosphane dichloropalladium (253 mg, 0.2 mmol) in N, N-dimethylformamide (100 mL) was heated at 110 C for 12 h under N2 atmosphere. After cooling, the mixture was filtered. The filtrate was diluted with water (40 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with water (10mL), brine (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 10% ethyl acetate in petroleum ether) to give tert-butyl (E)-4-(3-amino-6-methoxy-2- pyridyl)but-3- enoate (2.6 g, 50%) as a yellow oil, used in the next step without further purification.