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

HRID 1183971Notes

Reaction equation

HRID 1183971 reaction equation
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

Participants

7

Reactant 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

Product 1

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

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

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, 10:1 mixture) 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, 3H) 1.71-1.99 (m, 3H) 2.32-2.44 (m, 1H) 2.44-2.57 (m, 1H) 3.18 (d, J=2.93 Hz, 3H) 3.54-3.66 (m, 1H) 3.97-4.10 (m, 1H) 4.11-4.25 (m, 1H) 4.25-4.38 (m, 1H) 5.16 (d, J=15.81 Hz, 1H) 6.48 (dd, J=6.93, 1.27 Hz, 1H) 6.76 (s, 1H) 7.12 (t, J=8.59 Hz, 2H) 7.39 (d, J=7.02 Hz, 1H) 7.47-7.57 (m, 2H) 12.15 (d, J=7.42 Hz, 1H)

Workup

  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)

Sources & evidence

ORD record
ord-86ea9ce1287d4dfda503c246b5e3474c
Source dataset
uspto-grants-2014_03
Patent number
US08664401B2

Reaction notes

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