General procedure for the synthesis of methyl 6-amino-3-bromopyridine-2-carboxylate and methyl 5-bromo-6-aminopyridine-2-carboxylate from methyl 6-aminopyridine-2-carboxylate:
(d) Synthesis of methyl 6-amino-5-bromopyridine-2-carboxylate: to a solution of methyl 6-aminopyridine-2-carboxylate (10 g, 66.0 mmol) in chloroform (450 mL) was slowly added a solution of bromine (3.4 mL, 66.0 mmol) in chloroform (100 mL) at room temperature, and the reaction mixture was stirred for 40 hours. After completion of the reaction, the reaction mixture was diluted with chloroform and washed sequentially with saturated sodium thiosulfate solution and water. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography using ethyl acetate/hexane as eluent to afford methyl 6-amino-3-bromopyridine-2-carboxylate as a yellow solid (3.3 g, 22% yield). Mass spectrum (ESI) m/e: 231.0 [M+H]+. 1H NMR (CDCl3, 400MHz): δ (ppm) = 7.76 (d, J = 7.88Hz, 1H), 7.34 (d, J = 7.92Hz, 1H), 5.23 (s, 2H), 3.94 (s, 3H).
d) Isolation of methyl 6-amino-3-bromopyridine-2-carboxylate: In step d) above, the isomer methyl 6-amino-3-bromopyridine-2-carboxylate (3.0 g, 19% yield) was also isolated as a by-product. Mass spectrum (ESI) m/e: 231.2 [M+H]+. 1H NMR (CDCl3, 400MHz): δ (ppm) = 7.60 (d, J = 8.72Hz, 1H), 6.47 (d, J = 7.88Hz, 1H), 4.71 (s, 2H), 3.94 (s, 3H).
