Step-1: Synthesis of methyl 5-bromo-6-methoxynicotinate: ethyl 5,6-dibromonicotinate (5.0 g, 16.2 mmol, 1.0 eq.) was dissolved in anhydrous methanol (5 mL) under the protection of nitrogen and sodium methanolate (2.18 g, 40.5 mmol, 2.5 eq.) was added slowly. The reaction mixture was transferred to a sealed tube and heated and stirred at 85 °C in an oil bath for 48 hours. After completion of the reaction, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The crude product was dissolved in water (20 mL) and extracted with ethyl acetate (50 mL) to separate the organic layer. The aqueous layer was extracted twice more with ethyl acetate (2 x 50mL). The organic layers were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: gradient elution of ethyl acetate/hexane) to obtain the target product 5-bromo-6-methoxynicotinic acid methyl ester in the form of a white solid of 1.55 g, yield 39%. The structure of the product was confirmed by 1H NMR (400 MHz, CDCl3) and ESI-MS: 1H NMR δ 8.76 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 4.09 (s, 3H), 3.93 (s, 3H); ESI-MS m/z 246, 248 [M+H]+.
