Hydrochloric Acid → HCID 57464043, compound

Participants

Reaction Conditions

Reaction Steps

To a solution of (4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(piperidin-4-yl)pyrrolidin-2-one acetate (159 mg, 0.44 mmol, 1.2 equiv.) in MeOH was added Dowex resin (550A ion exchange) to free-base the amine. The resin was filtered and the filtrate was concentrated to an oil. To a solution of this oil in CH3CN (1.9 mL) was added 2-[4-(2-bromoethoxy)phenoxy][1,3]thiazolo[4,5-b]pyridine (130 mg, 0.37 mmol) and N,N-diisopropylethylamine (97 μL, 0.56 mmol, 1.5 equiv.). The resulting solution was stirred at 70° C. for 20 h. The solution was then cooled to rt and partitioned between satd. aq. NaHCO3 (20 mL) and CH2Cl2 (20 mL). The organic layer was washed with brine (20 mL), dried, filtered, and concentrated to give the crude product as a dark orange solid. To a solution of this oil (185 mg, 0.325 mmol) in CH2Cl2 (3.3 mL) was added HCl (4 M in dioxane, 1.79 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 (39 mg, 26%). 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.7, 1H), 8.00 (dd, J=7.9, 1.6, 1H), 7.35-7.30 (m, 2H), 7.19 (dd, J=7.9, 4.9, 1H), 6.97-6.93 (m, 2H), 4.36-4.27 (m, 1H), 4.16-4.07 (m, 2H), 4.05-3.92 (m, 1H), 3.44-3.35 (m, 1H), 3.28-3.19 (m, 1H), 3.13-3.03 (m, 2H), 2.87-2.79 (m, 1H), 2.70-2.64 (m, 1H), 2.51-2.40 (m, 1H), 2.32-2.20 (m, 2H), 1.97-1.75 (m, 3H), 1.74-1.69 (m, 2H). MS (ESI): mass calcd. for C23H26N4O4S, 454.2; m/z found, 455.1 [M+H]+.

Provenance & Evidence