Imidazo[1,2-a]pyridin-3-carboxaldehyde

Synthesis

Freshly distilled phosphorus trichloride (61 mL, 0.65 mol) was slowly added to N,N-dimethylformamide (120 mL, 1.55 mol) at 2 °C. After controlling the reaction temperature to gradually increase to room temperature, the reaction system was again cooled to 2 °C. Subsequently, a solution of N,N-dimethylformamide (60 mL) of imidazo[1,2-a]pyridine (10 g, 0.085 mol) was added dropwise. The reaction mixture was slowly warmed to 105 °C, followed by further warming to 140 °C. The reaction temperature was stabilized at 120 °C by removing the oil bath. Heating was continued at this temperature for 45 minutes, after which the temperature was reduced to 85 °C and continued for 2.5 hours. Upon completion of the reaction, the mixture was cooled and poured into ice-cooled 5% hydrochloric acid (600 mL) and the pH was adjusted with 20% sodium hydroxide solution to 9. The resulting solution was extracted with dichloromethane (1200 mL) overnight. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove the solvent. The crude product was washed with water (5 x 15 mL) and dried again to give 3.49 g of imidazo[1,2-a]pyridine-3-carbaldehyde in 31% yield.

References

[1] Farmaco, Edizione Scientifica, 1981, vol. 36, # 12, p. 994 - 1003
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 9, p. 3454 - 3464
[3] European Journal of Medicinal Chemistry, 2011, vol. 46, # 10, p. 4820 - 4826
[4] Journal of Medicinal Chemistry, 1996, vol. 39, # 14, p. 2856 - 2859
[5] Patent: WO2005/66132, 2005, A1. Location in patent: Page/Page column 89-90