Chlorotrimethylsilane → (4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl)methyl acetate

HRID 45124

反応式

HRID 45124 の反応式
BrCCBr.C[Si](Cl)(C)C.[C:10]([O:13][CH2:14]Br)(=[O:12])[CH3:11].[Br-].C(OC[Zn+])(=O)C.Cl[C:24]1[N:29]=[C:28]([O:30][C:31]2[C:32]([F:41])=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35]([CH3:40])=[CH:34]3)[CH:27]=[CH:26][N:25]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[NH4+].[Cl-]>CN(C=O)C.[Zn].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:10]([O:13][CH2:14][C:24]1[N:29]=[C:28]([O:30][C:31]2[C:32]([F:41])=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35]([CH3:40])=[CH:34]3)[CH:27]=[CH:26][N:25]=1)(=[O:12])[CH3:11]

参加物

11

反応物 7

HCID 6397ChlorotrimethylsilaneHCID 78391,2-DibromoethaneHCID 25517Ammonium ChlorideHCID 68536Bromomethyl acetateHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 866430875-(2-chloropyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indoleHCID 178476619HCID 178476619、化合物

生成物 1

HCID 67433093(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl)methyl acetate

試薬・触媒・溶媒 3

HCID 23994Zinc触媒3 回HCID 167845palladium(II) acetate触媒HCID 6228Dimethylformamide溶媒2 回

反応条件

温度
60 °C

実験手順

1,2-Dibromoethane (425 μL, 5.0 mmol) is added to a suspension of zinc powder (2.83 g, 43.2 mmol) in dry DMF (8 mL). The reaction mixture is heated at 60° C. for 10 min, then cooled to room temperature. TMSCl (500 μl, 4.0 mmol) is added (caution: exothermic!) and the resulting mixture is sonicated for 30 min. Zinc powder is allowed to settle and the supernatant is removed by syringe. DMF (8 mL) is added, followed by bromomethyl acetate (2.12 mL, 21.61 mmol). The mixture is stirred at 23° C. for 2.5 h. Zinc is allowed to settle and the solution of acetoxymethylzinc bromide is then transferred to a solution of 5-(2-chloropyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole (2.00 g, 7.20 mmol), palladium acetate (0.081 g, 0.360 mmol), and S-phos (0.355 g, 0.864 mmol) in DMF (10 mL) at 23° C. The resulting mixture is stirred at 23° C. for 15 h. Saturated aqueous NH4Cl (100 mL) is added and the mixture is then partitioned between EtOAc (150 mL) and water (150 mL). The aqueous layer is extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine (60 mL), dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (0-100% EtOAc/heptane) to give (4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl)methyl acetate.

後処理

  1. temperaturecooled to room temperature
  2. customthe resulting mixture is sonicated for 30 min
  3. customthe supernatant is removed by syringe
  4. additionDMF (8 mL) is added
  5. stirringThe resulting mixture is stirred at 23° C. for 15 h
  6. customthe mixture is then partitioned between EtOAc (150 mL) and water (150 mL)
  7. extractionThe aqueous layer is extracted with EtOAc (2×100 mL)
  8. washThe combined organic layers are washed with brine (60 mL)
  9. dry with materialdried (Na2SO4)
  10. concentrationconcentrated
  11. customThe residue is purified by silica gel chromatography (0-100% EtOAc/heptane)

出典と根拠

ORDレコード
ord-fa039d5b6d61430db2ae60cf04b1721a
出典データセット
uspto-grants-2013_09
特許番号
US08541432B2

関連ノート

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