Tetrahydrofuran → 1-{[2-(5-{1-[4-(Cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2h-pyran-4-yl)ethyl}-1h-pyrrol-2-yl)-1,3-thiazol-5-yl]methyl}piperidin-4-one hydrochloride

Temperatur

0 °C

To a mixture of [2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]methanol (0.30 g), N,N-dimethylformamide (two drops) and tetrahydrofuran (6 mL) was added thionyl chloride (0.09 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr and concentrated. The obtained residue was dissolved in tetrahydrofuran (2 mL) and the solution was added to a mixture of piperidine-4,4-diol hydrochloride (0.19 g), potassium carbonate (0.17 g) and N,N-dimethylformamide (6 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography to give a yellow amorphous solid from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). The obtained amorphous solid was dissolved in ethyl acetate, and 4M hydrogen chloride-ethyl acetate solution (1.0 mL) was added. The precipitated crystals were collected by filtration, and dried to give the title compound (0.21 g, yield 57%) as yellow crystals. melting point 146-148° C. MS: 554 (MH+).

1. concentrationconcentrated
2. dissolutionThe obtained residue was dissolved in tetrahydrofuran (2 mL)
3. additionthe solution was added to a mixture of piperidine-4,4-diol hydrochloride (0.19 g), potassium carbonate (0.17 g) and N,N-dimethylformamide (6 mL) at 0° C
4. stirringThe reaction mixture was stirred at room temperature overnight
5. additionwater was added
6. extractionthe mixture was extracted with ethyl acetate
7. washThe ethyl acetate layer was washed with saturated brine
8. dry with materialdried (MgSO4)
9. concentrationconcentrated
10. customto give a yellow amorphous solid from a fraction
11. washeluted with tetrahydrofuran-hexane (3:1, volume ratio)
12. dissolutionThe obtained amorphous solid was dissolved in ethyl acetate
13. addition4M hydrogen chloride-ethyl acetate solution (1.0 mL) was added
14. filtrationThe precipitated crystals were collected by filtration
15. customdried

ORD-Eintrag

ord-4afecf4946fb4deb945e45a841916e7e

Quelldatensatz

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08318746B2