1. diisopropylamine (5.7 g, 28.4 mmol, 2.0 eq.) was dissolved in anhydrous tetrahydrofuran (200.0 mL), and the reaction system was cooled to -60°C to -65°C. The reaction system was then cooled to -60°C to -65°C. The reaction system was then cooled to -60°C to -65°C, and the reaction system was cooled to -65°C.
2. n-Butyllithium (35.5 mL, 56.8 mmol, 2.0 eq.) was slowly added dropwise to the above solution with stirring.
3. maintain the temperature at -60°C to -65°C and continue to stir the reaction mixture for 30 minutes.
4. Slowly add a solution of 3-bromo-5-fluoropyridine (5.0 g, 28.4 mmol, 1.0 eq.) in anhydrous tetrahydrofuran (50.0 mL) at the same temperature and stir for 30 min.
5. N,N-dimethylformamide (2.5 g, 34.1 mmol, 1.2 eq.) was added in a single addition and stirred at -60°C to -65°C for 30 min.
6. Upon completion of the reaction, the reaction was quenched with methanol followed by the addition of an aqueous ammonium chloride solution.
7. The reaction mixture was diluted with ethyl acetate (200.0 mL) and extracted with ethyl acetate (200.0 mL × 3).
8. The organic phases were combined, washed with saturated saline and concentrated under reduced pressure.
9. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give 3-bromo-5-fluoroisonicotinaldehyde (3.5 g, 60.3% yield) as a brown oil.
10. The product was analyzed by liquid chromatography-mass spectrometry (LCMS) with a calculated (M + H+) m/z of 204.1 and a measured value of 204.2.
