Synthesis
a) Under nitrogen protection, 5-chloro-2-cyanopyridine (10.7 g, 77 mmol) was dissolved in a solvent mixture of ether (65 mL) and tetrahydrofuran (THF, 35 mL). The reaction mixture was cooled to an internal temperature of -63 °C. Methylmagnesium bromide (3M THF solution, 35 mL, 105 mmol) was added slowly over 30 minutes. After addition, the reaction mixture was continued to be stirred at -60 °C for 45 min, followed by slow warming to room temperature. THF (50 mL) was added to dissolve any precipitate that may have formed and the reaction mixture was stirred for 1 hour. Subsequently, 2M aqueous hydrochloric acid (100 mL) was added and stirring was continued for 4 hours. The pH of the reaction mixture was adjusted with aqueous sodium bicarbonate to 7. The organic and aqueous phases were separated and the product was extracted from the aqueous phase with dichloromethane (DCM). The organic extracts were combined, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by fast column chromatography (eluent: heptane/ethyl acetate gradient) to afford 7.9 g (64% yield) of 1-(5-chloropyridin-2-yl)ethanone.1H NMR (300 MHz, CDCl3) δ ppm: 8.62 (m, 1H), 8.00 (m, 1H), 7.80 (m, 1H), 2.70 (s, 3H).
References
[1] Patent: WO2008/39139, 2008, A1. Location in patent: Page/Page column 26
[2] Patent: WO2008/39138, 2008, A1. Location in patent: Page/Page column 28
