2-Fluorophenol → 1,1-Dimethylethyl (2S)-4-({4-[({6-[(2-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate

HRID 534736Notes

Reaction equation

HRID 534736 reaction equation
Cl[C:2]1[N:7]=[CH:6][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])=[CH:4][CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][C:2]1[N:7]=[CH:6][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])=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 97072-FluorophenolHCID 11430Potassium CarbonateHCID 592622291,1-Dimethylethyl (2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate

Product 1

HCID 592622161,1-Dimethylethyl (2S)-4-({4-[({6-[(2-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylateYield 32.6%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
80 °C

Procedure

1,1-Dimethylethyl (2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D54) (0.1 g, 0.218 mmol) and 2-fluorophenol (0.025 g, 0.436 mmol) were dissolved in DMF (5 mL). Potassium carbonate (0.06 g, 0.436 mmol) was added and the mixture was heated to 80° C. overnight then at 130° C. for 7 h. The mixture was left to stand at room temperature overnight and the solvent removed under vacuum. The residue was partitioned between EtOAc and water. The organic layer was dried and concentrated to produce a brown oil. The crude product was purified by MDAP to yield the formic acid salt. The salt was taken up in DCM and washed with sat. NaHCO3. The DCM layer was dried and concentrated to yield the title compound as a colourless oil (0.038 g). δH (CDCl3, 400 MHz) 8.02 (1H, d), 7.68 (1H, dd), 7.23 (2H, d), 7.15 (4H, m), 6.98 (2H, d), 6.78 (1H, d), 4.18 (1H, br.s), 3.80 (1H, d), 3.48 (3H, s), 3.46 (1H, d), 3.33 (1H, d), 3.08 (1H, td), 2.69 (1H, d), 2.51 (1H, d), 2.10 (1H, dd), 1.98 (1H, m), 1.46 (9H, s), 1.20 (3H, d). MS (ES): MH+ 535.3.

Workup

  1. waitThe mixture was left
  2. waitto stand at room temperature overnight
  3. customthe solvent removed under vacuum
  4. customThe residue was partitioned between EtOAc and water
  5. customThe organic layer was dried
  6. concentrationconcentrated
  7. customto produce a brown oil
  8. customThe crude product was purified by MDAP
  9. customto yield the formic acid salt
  10. washwashed with sat. NaHCO3
  11. dry with materialThe DCM layer was dried
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-ae91dddc8b4541a988d815f0ef1c027d
Source dataset
uspto-grants-2014_10
Patent number
US08853218B2

Reaction notes

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