2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → tert-butyl (2-chloro-4-{2-[(1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetate

HRID 1474689Notes

Reaction equation

HRID 1474689 reaction equation
Br[C:2]1[CH:28]=[CH:27][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]([CH2:24][O:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][C:3]=1[Cl:29].[Cl-].[C:31]([O:35][C:36](=[O:39])[CH2:37][Zn+])([CH3:34])([CH3:33])[CH3:32].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.C(OCC)(=O)C.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]>[Cl: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]([CH2:24][O:25][CH3:26])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:27]=[CH:28][C:2]=1[CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:39]

Participants

7

Reactant 3

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 1176785802-(4-{(1R,2S)-2-[2-(4-bromo-3-chlorophenoxy)ethyl]cyclopropyl}piperidin-1-yl)-5-(methoxymethyl)pyrimidineHCID 178451183HCID 178451183, compound

Product 1

HCID 117684439tert-butyl (2-chloro-4-{2-[(1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetate

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 2-(4-{(1R,2S)-2-[2-(4-bromo-3-chlorophenoxy)ethyl]cyclopropyl}piperidin-1-yl)-5-(methoxymethyl)pyrimidine (0.91 g, 1.89 mmol) in THF (10 ml) was added 2-tert-butoxy-2-oxoethylzinc chloride (9.46 ml, 4.73 mmol). Nitrogen gas bubbled through the mixture for 10 min. then Pd2(dba)3 (0.087 g, 0.189 mmol) and X-PHOS (0.090 g, 0.189 mmol) were added and the resulting mixture heated at 60° C. for 30 min. The mixture was cooled, diluted with ethyl acetate (20 mL), washed with aqueous ammonium chloride (saturated, 1×15 mL), dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 50M, using a gradient eluant of EtOAc/Hexane (0-50%) to afford the title compound. LC/MS (m/z): 516 (M+H)+.

Workup

  1. customNitrogen gas bubbled through the mixture for 10 min.
  2. temperatureThe mixture was cooled
  3. washwashed with aqueous ammonium chloride (saturated, 1×15 mL)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. customthe solvent evaporated under reduced pressure
  7. customThe residue was purified by column chromatography on silica gel Biotage 50M

Sources & evidence

ORD record
ord-fdd3658339474514ae8a7fb1f2ba7349
Source dataset
uspto-grants-2015_04
Patent number
US09018224B2

Reaction notes

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