Water → (2R)-2-Methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4-[4'-(tetrahydro-2H-pyran-2-yloxy)biphenyl-4-yl]butanamide

HRID 533570Notes

Reaction equation

HRID 533570 reaction equation
C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@@:8]([S:36]([CH3:39])(=[O:38])=[O:37])([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)[C:9]([NH:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)=[O:10].Br[C:41]1[CH:53]=[CH:52][C:44]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)=[CH:43][CH:42]=1.O>O1CCOCC1.C(Cl)Cl.[Pd+2]>[CH3:7][C@@:8]([S:36]([CH3:39])(=[O:37])=[O:38])([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:41]2[CH:53]=[CH:52][C:44]([O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)=[CH:43][CH:42]=2)=[CH:25][CH:26]=1)[C:9]([NH:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)=[O:10]

Participants

8

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 46464362-(4-Bromophenoxy)tetrahydro-2H-pyranHCID 56950325(2R)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanamide

Product 1

HCID 86668786(2R)-2-Methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4-[4'-(tetrahydro-2H-pyran-2-yloxy)biphenyl-4-yl]butanamide

Reagents, catalysts & solvents 3

HCID 105144Allyl(1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)chloropalladium(II)CatalystHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

Palladium (II) EnCat (575 mg, 0.22 mmol) was added to a mixture of potassium carbonate (892 mg, 3.1 mmol), (2R)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanamide (1.01 g, 2.1 mmol), (i.e. compound VIIa, which was prepared as in Preparation 8) and 2-(4-bromophenoxy)tetrahydro-2H-pyran (819 mg, 3.18 mmol) in dioxane:water (20 mL, 1:1) in a 50 mL flask and the reaction was heated at 90° C. overnight. The reaction was filtered and the resin was washed with ethyl acetate (50 mL) and water (50 mL). The organic layer was separated and aqueous layer extracted with ethyl acetate (2×100 mL). The combined organics were washed with saturated aqueous sodium bicarbonate (100 mL), dried (MgSO4), filtered and concentrated in vacuo to furnish the crude product. The material was dissolved in a minimum amount of DCM and loaded onto an Analogix SF25-40 g column and eluted with 100% heptane (500 mL) followed by increasing EtOAc in heptane 20%-30%-50% over 500 mL volumes. The title compound was obtained as a white solid (830 mg, 74.4%) LC-MS m/z 530.8 (M−1).

Workup

  1. filtrationThe reaction was filtered
  2. washthe resin was washed with ethyl acetate (50 mL) and water (50 mL)
  3. customThe organic layer was separated
  4. extractionaqueous layer extracted with ethyl acetate (2×100 mL)
  5. washThe combined organics were washed with saturated aqueous sodium bicarbonate (100 mL)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto furnish the crude product
  10. washeluted with 100% heptane (500 mL)
  11. temperatureby increasing EtOAc in heptane 20%-30%-50% over 500 mL volumes

Sources & evidence

ORD record
ord-bd3aea9004ff4d62b616f77e528da796
Source dataset
uspto-grants-2014_10
Patent number
US08853258B2

Reaction notes

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