2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → Tert-butyl 2-(2,6-difluoro-4-(2-((1S,2R)-2-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethoxy)phenyl)acetate

HRID 1474721Notes

Reaction equation

HRID 1474721 reaction equation
Br[C:2]1[C:27]([F:28])=[CH:26][C:5]([O:6][CH2:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:29].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Br-].[C:65]([O:69][C:70](=[O:73])[CH2:71][Zn+])([CH3:68])([CH3:67])[CH3:66]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:29][C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:26]=[C:27]([F:28])[C:2]=1[CH2:71][C:70]([O:69][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:73]

Participants

6

Reactant 3

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 1176783652-(4-((1R,2S)-2-(2-(4-bromo-3,5-difluorophenoxy)ethyl)cyclopropyl)piperidin-1-yl)-5-methoxypyrimidineHCID 178451181HCID 178451181, compound

Product 1

HCID 89583787Tert-butyl 2-(2,6-difluoro-4-(2-((1S,2R)-2-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethoxy)phenyl)acetate

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To 2-(4-((1R,2S)-2-(2-(4-bromo-3,5-difluorophenoxy)ethyl)cyclopropyl)piperidin-1-yl)-5-methoxypyrimidine (1.86 g, 3.97 mmol) in THF (5 ml) was added tris(dibenzylideneacetone)dipalladium(0) (0.364 g, 0.397 mmol) and X-PHOS (0.379 g, 0.794 mmol), followed by (2-tert-butoxy-2-oxoethyl)zinc(II) bromide (0.5 M in ethyl ether, 23.83 ml, 11.91 mmol). The mixture was degassed under N2 for 10 min then heated at 60° C. overnight. The mixture was diluted with sat. NH4Cl (50 ml), and the aqueous phase extracted with EtOAc (50 ml×2). The organic fractions were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g SNAP, 5˜30% EtOAc in hexane) to afford the titled compound. LC/MS (m/z): 504 (M+H)+. Rf was 0.28 @ 25% EtOAc in hexanes (blue spot on CAM stain)

Workup

  1. customThe mixture was degassed under N2 for 10 min
  2. additionThe mixture was diluted with sat. NH4Cl (50 ml)
  3. extractionthe aqueous phase extracted with EtOAc (50 ml×2)
  4. washwashed with brine
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel column chromatography (50 g SNAP, 5˜30% EtOAc in hexane)

Sources & evidence

ORD record
ord-498412829ae744608e75a5f689840298
Source dataset
uspto-grants-2015_04
Patent number
US09018224B2

Reaction notes

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