Water → (2R)-4-[4-(4-fluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

HRID 84262Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 84262
C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.I[C:18]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C@@:26]([CH3:41])([S:37]([CH3:40])(=[O:39])=[O:38])[C:27]([NH:29][O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)=[O:28])[C:20](=[O:42])[CH:19]=1.O>O1CCOCC1.[Pd]>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][C@@:26]([CH3:41])([S:37]([CH3:40])(=[O:39])=[O:38])[C:27]([NH:29][O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)=[O:28])[C:20](=[O:42])[CH:19]=2)=[CH:10][CH:9]=1

Komponenten

7

Edukt 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 2856454-Fluorophenylboronic acidHCID 57326595(2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

Produkt 1

HCID 86671944(2R)-4-[4-(4-fluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 23938PalladiumKatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

Pd EnCat™ (200 mg, 0.06 mmol) was added to a mixture of potassium carbonate (250 mg, 1.81 mmol), (4-fluorophenyl)boronic acid (84 mg, 0.602 mmol), and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, which may be produced as in Preparation 2 B, (300 mg, 0.602 mmol) in dioxane:water (5.5 mL, 10:1mixture) in a 25 mL round bottom flask. The flask was heated overnight at 80° C. The reaction was cooled to ambient temperature and filtered through celite and washed with ethyl acetate (20 mL). The crude material was concentrated, and purified by chromatography on silica gel (gradient: 100:0 dichloromethane:methanol to 95:5 dichloromethane:methanol) to provide title compound as a viscous, foamy oil. Yield: 257 mg, 91.5%. MS (APCI) m/z 467.6 (M+H) 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.54-1.65 (m, 3H) 1.68 (d, J=2.34 Hz, 3 H) 1.71-1.99 (m, 3 H) 2.32-2.44 (m, 1 H) 2.44-2.57 (m, 1 H) 3.18 (d, J=2.93 Hz, 3 H) 3.54-3.66 (m, 1 H) 3.97-4.10 (m, 1 H) 4.11-4.25 (m, 1 H) 4.25-4.38 (m, 1 H) 5.16 (d, J=15.81 Hz, 1 H) 6.48 (dd, J=6.93, 1.27 Hz, 1 H) 6.76 (s, 1 H) 7.12 (t, J=8.59 Hz, 2 H) 7.39 (d, J=7.02 Hz, 1 H) 7.47-7.57 (m, 2 H) 12.15 (d, J=7.42 Hz, 1 H)

Aufarbeitung

  1. temperatureThe reaction was cooled to ambient temperature
  2. filtrationfiltered through celite
  3. washwashed with ethyl acetate (20 mL)
  4. concentrationThe crude material was concentrated
  5. custompurified by chromatography on silica gel (gradient: 100:0 dichloromethane:methanol to 95:5 dichloromethane:methanol)

Quellen und Nachweise

ORD-Eintrag
ord-f1ef752e41674accad119d4ee234dfac
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08846933B2

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