Uses
3,5-Dimethyl-1H-pyrrole-2-carboxaldehyde is an intermediate used in the synthesis of a series of anaplastic lymphoma kinase (ALK) inhibitors, a new target for therapy of non-small-cell lung cancer (NSCLC).
Synthesis
General procedure for the synthesis of 3,5-dimethyl-2-pyrrolecarboxaldehyde from 2,4-dimethylpyrrole:
A. Under argon protection, dimethylformamide (4.5 mL, 57.8 mmol) was cooled to 0 °C, followed by dropwise addition of phosphorus trichloride (57.8 mmol) over 5 min. The cooling bath was removed and after 15 minutes of reaction, 1,2-dichloroethane (15 mL) was added. The reaction mixture was cooled again to 0 °C and a 1,2-dichloroethane (15 mL) solution of 2,4-dimethylpyrrole (52.6 mmol) was added dropwise over 15 min. The reaction mixture was heated to reflux maintained for 15 min and then cooled to room temperature. A solution of sodium acetate (24 g) in water (75 mL) was slowly added to the reaction mixture and the resulting mixture was heated to reflux again for 20 minutes. After the reaction mixture was cooled to room temperature, it was diluted with dichloromethane and the aqueous phase was washed with dichloromethane (2 x 50 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuum. The crude product was purified by silica gel column chromatography with hexane solution of 10% ethyl acetate as eluent to give 5.2 g (80% yield) of the target product 3,5-dimethyl-2-pyrrolecarboxaldehyde. [M + H]+ = 124.1, [M - H]- = 122.0.
References
[1] Patent: US6982265, 2006, B1. Location in patent: Page/Page column 28
[2] Gazzetta Chimica Italiana, 1934, vol. 64, p. 778,782
