4-Fluorophenol → 1,1-Dimethylethyl (2S)-4-({4-[({5-[(4-fluorophenyl)oxy]-2-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate

HRID 644725Notes

Reaction equation

HRID 644725 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[N:6][CH:7]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1.[Cu]Cl>[F:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[N:6][CH:7]=2)=[CH:36][CH:35]=1

Participants

7

Reactant 4

HCID 97324-Fluorophenol2×HCID 10796Cesium carbonate2×HCID 707002,2,6,6-Tetramethyl-3,5-heptanedione2×HCID 592622381,1-Dimethylethyl (2S)-4-({4-[[(5-bromo-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate

Product 1

HCID 592622281,1-Dimethylethyl (2S)-4-({4-[({5-[(4-fluorophenyl)oxy]-2-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylateYield 75.9%

Reagents, catalysts & solvents 2

HCID 62652Cuprous chlorideCatalyst2×HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
120 °C

Procedure

1,1-Dimethylethyl (2S)-4-({4-[[(5-bromo-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D72) (0.2 g, 0.397 mmol), 4-fluorophenol (0.089 g, 0.794 mmol), cesium carbonate (0.259 g, 0.794 mmol) and 2,2,6,6-tetramethyl-3,5-heptanedione (TMHD) (0.008 g, 0.040 mmol) were combined in NMP (3 mL) under argon. Copper (I) chloride (0.02 g, 0.199 mmol) was added and the mixture heated at 120° C. overnight. A second portion of 4-fluorophenol, copper (I) chloride, cesium carbonate and TMHD was added and heating continued at 120° C. overnight. After cooling to room temperature, the mixture was partially concentrated, the residue was taken up in EtOAc and washed with saturated aqueous NaHCO3 and water. The organic layer was dried and concentrated to give the crude product which was purified by column chromatography. Elution with 0-50% ethyl acetate/petroleum ether yielded the title compound as a yellow oil (0.161 g). δH (CDCl3, 400 MHz) 8.04 (1H, br.s), 7.49 (1H, br.d), 7.20 (2H, d), 7.00 (7H, m), 4.17 (1H, br.s), 3.79 (1H, d), 3.51 (3H, s), 3.47 (1H, d), 3.33 (1H, d), 3.08 (1H, td), 2.69 (1H, d), 2.51 (1H, d), 2.10 (1H, dd), 1.99 (1H, m), 1.46 (9H, s), 1.19 (3H, d). MS (ES): MH+ 535.4.

Workup

  1. temperatureheating
  2. temperatureAfter cooling to room temperature
  3. concentrationthe mixture was partially concentrated
  4. washwashed with saturated aqueous NaHCO3 and water
  5. customThe organic layer was dried
  6. concentrationconcentrated
  7. customto give the crude product which
  8. customwas purified by column chromatography
  9. washElution with 0-50% ethyl acetate/petroleum ether

Sources & evidence

ORD record
ord-236dfc630b4549efb058e2c63da28fc4
Source dataset
uspto-grants-2010_04
Patent number
US07700599B2

Reaction notes

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