Hydrochloric Acid → 2-Chloro-5-[(1-methyl-1H-imidazol-5-yl)carbonyl]pyridine

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Reaction Steps

To a 250-mL 3-necked round-bottom flask containing a solution of 1-methyl-1H-imidazole (5.00 g, 60.9 mmol) and tetrahydrofuran (40 mL) was added n-BuLi (29.3 mL, 73.3 mmol, 2.5 M in hexanes) at −78° C., and stirred for 45 minutes. To this mixture Et3SiCl (9.15 g, 61.0 mmol) was added, and stirring was continued for 1 hour at −78° C. To the mixture was added n-BuLi (26.0 mL, 65.0 mmol, 2.5 M in hexanes). After stirring for another 45 minutes, a solution of 6-chloro-N-methoxy-N-methylpyridine-3-carboxamide (8.13 g, 40.5 mmol, Intermediate 4, step b) in tetrahydrofuran (20 mL) was added at −78° C. The resulting mixture was allowed to warm up to room temperature overnight. To the mixture was added 1.0 M aqueous HCl until pH 3-4. After stirring for 2 hours at room temperature, the mixture was basified with 1.5 M aqueous sodium hydroxide until pH 9-10. The resulting mixture was diluted with 100 mL of H2O and extracted with 3×100 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with dichloromethane/methanol (100:0 to 15:1) to afford the title compound as a yellow solid.

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