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

HRID 644725노트

반응식

HRID 644725 반응식
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

참가 물질

7

반응물 4

HCID 97324-Fluorophenol2회HCID 10796Cesium carbonate2회HCID 707002,2,6,6-Tetramethyl-3,5-heptanedione2회HCID 592622381,1-Dimethylethyl (2S)-4-({4-[[(5-bromo-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate

생성물 1

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

시약·촉매·용매 2

HCID 62652Cuprous chloride촉매2회HCID 13387N-methyl-2-pyrrolidone용매

반응 조건

온도
120 °C

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-236dfc630b4549efb058e2c63da28fc4
출처 데이터셋
uspto-grants-2010_04
특허 번호
US07700599B2

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