Hydrochloric Acid → HCID 57464043, compound

Temperature

70 °C

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]+.

1. filtrationThe resin was filtered
2. concentrationthe filtrate was concentrated to an oil
3. temperatureThe solution was then cooled to rt
4. custompartitioned between satd
5. washThe organic layer was washed with brine (20 mL)
6. customdried
7. filtrationfiltered
8. concentrationconcentrated
9. customto give the crude product as a dark orange solid
10. stirringThe reaction was stirred at rt for 2.5 h
11. concentrationconcentrated
12. dissolutionThe residue was dissolved in water (20 mL)
13. extractionThe mixture was then extracted with CH2Cl2 (2×15 mL)
14. washthe organic layers (CH2Cl2 and EtOAc) were individually washed with water (30 mL each)
15. customThe combined organic layers were dried
16. filtrationfiltered
17. concentrationconcentrated
18. customto give the crude product as a white solid
19. customThe crude product was purified

ORD record

ord-70285fa134a54498831a300127fb4453

Source dataset

uspto-grants-2011_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07939527B2