Synthesis
To a solution of 3,5-dimethoxypyridine (3.6 g, 25.90 mmol, 1 eq.) in tetrahydrofuran (THF, 80 mL) was slowly added n-butyllithium (BuLi, 3M hexane solution, 13.0 mL, 38.85 mmol, 1.5 eq.) at -20 °C. The reaction mixture was slowly warmed to 0 °C and stirred at this temperature for 30 minutes. Subsequently, the reaction system was cooled to -78 °C and N,N-dimethylformamide (DMF, 3.8 g, 51.8 mmol, 2 eq.) was added dropwise. The reaction mixture was gradually warmed to 0 °C and the reaction was quenched with saturated aqueous ammonium chloride (NH4Cl) and diluted with ethyl acetate (EtOAc). The aqueous phase was extracted twice with ethyl acetate (EtOAc). The organic phases were combined, washed with saturated saline (brine), dried over anhydrous sodium sulfate (Na2SO4) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a solvent mixture of ethyl acetate (EtOAc) and hexane as eluent to afford 3,5-dimethoxypyridine-4-carbaldehyde (2.7 g, 62% yield) as a yellow solid. Low resolution mass spectrometry (LRMS) showed (M+H)+ m/z 168.1.
References
[1] Patent: WO2013/102145, 2013, A1. Location in patent: Paragraph 0316
[2] Patent: US2015/344483, 2015, A1. Location in patent: Paragraph 0584; 0585
[3] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 3, p. 321 - 326
[4] Patent: WO2007/30582, 2007, A2. Location in patent: Page/Page column 89
