Diethyl Ether → Benzyl 4-{(1R,2S)-2-[2-(2-tert-butoxy-2-oxoethyl-2,5-difluorophenoxy)ethyl]cyclopropyl}piperidine-1-carboxylate

HRID 1474714Notes

Reaction equation

HRID 1474714 reaction equation
Br[C:2]1[C:29]([F:30])=[CH:28][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]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=[C:4]([F:31])[CH:3]=1.[Cl-].[C:33]([O:37]C(=O)C[Zn+])([CH3:36])([CH3:35])[CH3:34].[CH2:42]([O:44]CC)[CH3:43].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>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]>[C:33]([O:37][C:4]1([F:31])[C:3]([CH2:43][CH:42]=[O:44])=[CH:2][C:29]([F:30])=[CH:28][CH:5]1[O:6][CH2:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:16][CH2:17]1)([CH3:36])([CH3:35])[CH3:34]

Participants

7

Reactant 4

HCID 3283Diethyl EtherHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 70818516Benzyl 4-{(1R,2S)-2-[2-(4-bromo-2,5 difluorophenoxy)ethyl]cyclopropyl}piperidine-1-carboxylateHCID 178451183HCID 178451183, compound

Product 1

HCID 117678479Benzyl 4-{(1R,2S)-2-[2-(2-tert-butoxy-2-oxoethyl-2,5-difluorophenoxy)ethyl]cyclopropyl}piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
65 °C

Procedure

Benzyl 4-{(1R,2S)-2-[2-(4-bromo-2,5 difluorophenoxy)ethyl]cyclopropyl}piperidine-1-carboxylate (0.540 g, 1.09 mmol) in THF (5 ml) was added 0.5 M 2-tert-butoxy-2-oxoethylzinc chloride in diethyl ether (5.46 ml, 2.73 mmol), followed by Pd2(dba)3 (50 mg, 0.055 mmol) and 52 mg X-Phos. The vessel was evacuated and back filled with nitrogen (3×) and the mixture was heated at 65° C. overnight. Saturated ammonium chloride (10 ml) was added and the mixture extracted with EtOAc (15 ml). The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (Biotage SNAP column, 25 g) using a gradient 0-15% then 15% EtOAc in hexanes to afford the title compound. LC/MS (m/z): 552.4 (M+Na)+.

Workup

  1. customThe vessel was evacuated
  2. additionback filled with nitrogen (3×)
  3. additionSaturated ammonium chloride (10 ml) was added
  4. extractionthe mixture extracted with EtOAc (15 ml)
  5. customThe organic layer was separated
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. customThe residue was purified by column chromatography on silica gel (Biotage SNAP column, 25 g)

Sources & evidence

ORD record
ord-4cddd796ddf846608004cbbd855633d5
Source dataset
uspto-grants-2015_04
Patent number
US09018224B2

Reaction notes

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