In Step 6-iv of Scheme 6, 2,5-dibromo-3-methoxypyridine (Compound 1020, 5 g, 18.73 mmol) was dissolved in anhydrous tetrahydrofuran (THF, 94 mL), followed by the addition of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 2.16 g, 1.873 mmol). The reaction mixture was cooled in an ice bath and a 3:1 THF/toluene solution of methylmagnesium bromide (17.4 mL, 1.4 M, 24.35 mmol) was added slowly and dropwise. After removing the ice bath, the reaction mixture was heated to reflux. After stirring under reflux conditions for 1 hour, 3 mL of methylmagnesium bromide solution was added additionally. After continuing to stir at reflux for 20 minutes, 2 mL of methylmagnesium bromide solution was added again. The reaction mixture was continued to be stirred under reflux for 1 hour and subsequently cooled to room temperature. The organic layer was separated by adding ether and 1N hydrochloric acid (HCl) for quenching and washed with 1N HCl. The aqueous phase was extracted three times with ether. The aqueous phase was adjusted to alkaline with 2N sodium hydroxide (NaOH) and extracted three times with ethyl acetate. The ethyl acetate extracts were combined, dried with anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-25% ethyl acetate/hexane) to afford 5-bromo-3-methoxy-2-methylpyridine (Compound 1021, 2.7 g, 71% yield): ESMS (M + H) 202, 204.5-Bromo-2-ethyl-3-methoxypyridine was prepared using a similar method: ESMS (M + H) 216, 218. 1H NMR (CDCl3) δ 8.2 (d, 1H), 7.2 (d, 1H), 3.8 (s, 3H), 2.8 (q, 2H), 1.2 (t, 3H).
