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

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]+.

1. customThe reaction mixture was then partitioned between sat. aq. NaHCO3 (20 mL) and CH2Cl2 (20 mL)
2. washThe organic layer was washed with brine (20 mL)
3. customdried
4. filtrationfiltered
5. concentrationconcentrated to an orange oil
6. stirringThe reaction was stirred at rt for 2.5 h
7. concentrationconcentrated
8. dissolutionThe residue was dissolved in water (20 mL)
9. extractionThe mixture was then extracted with CH2Cl2 (2×15 mL)
10. washthe organic layers (CH2Cl2 and EtOAc) were individually washed with water (30 mL each)
11. customThe combined organic layers were dried
12. filtrationfiltered
13. concentrationconcentrated
14. customto give the crude product as a white solid
15. customThe crude product was purified

ORD record

ord-7092933e4a734f1b8168d7c420d05b29

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08357684B2