Hydrochloric Acid → (4r)-4-Hydroxy-1-{1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidin-4-yl}pyrrolidin-2-one

Participants

Reaction Steps

To a solution of (4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(piperidin-4-yl)pyrrolidin-2-one acetate (252 mg, 0.70 mmol, 1.2 equiv.) in DCE (3.1 mL) was added Et3N (98 μL, 0.70 mmol, 1.2 equiv.) and stirred at rt for 30 min to free-base the amine. To this solution was added 4-([1,3]thiazolo[4,5-b]pyridine-2-yloxy)benzaldehyde (150 mg, 0.585 mmol) and sodium triacetoxyborohydride (211 mg, 0.995 mmol, 1.7 equiv.). The mixture was stirred at rt for 17 h. The reaction mixture was then partitioned between sat. aq. NaHCO3 (20 mL) and CH2Cl2 (20 mL). The organic layer was washed with brine (20 mL), dried, filtered, and concentrated to an orange oil. To a solution of this oil (158 mg, 0.293 mmol) in CH2Cl2 (2.9 mL) was added HCl (4 M in dioxane, 1.62 mL, 22.0 equiv.). The reaction was stirred at rt for 2.5 h and then concentrated. The residue was dissolved in water (20 mL), and the pH adjusted to ˜pH 7 with 1 M aq. NaOH. The mixture was then extracted with CH2Cl2 (2×15 mL) followed by EtOAc (2×15 mL) and the organic layers (CH2Cl2 and EtOAc) were individually washed with water (30 mL each). The combined organic layers were dried, filtered and concentrated to give the crude product as a white solid. The crude product was purified using preparative reversed phase HPLC to afford the desired product as a white solid (51 mg, 41%). 1H NMR (500 MHz, CDCl3): 8.58 (dd, J=4.8, 1.7, 1H), 8.04 (dd, J=7.9, 1.7, 1H), 7.42-7.40 (m, 2H), 7.39-7.37 (m, 2H), 7.22 (dd, J=7.9, 4.8, 1H), 4.38-4.30 (m, 1H), 4.06-3.95 (m, 1H), 3.56-3.51 (m, 2H), 3.45-3.38 (m, 1H), 3.31-3.22 (m, 1H), 3.03-2.94 (m, 2H), 2.82-2.77 (m, 1H), 2.52-2.43 (m, 1H), 2.20-2.07 (m, 2H), 1.98-1.88 (m, 1H), 1.83-1.73 (m, 2H), 1.72-1.66 (m, 2H). MS (ESI): mass calcd. for C22H24N4O3S, 424.2; m/z found, 425.1 [M+H]+.

Provenance & Evidence