Phosphorus oxybromide → 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-(methylsulfonyl)quinazolin-4-amine

HRID 473190ノート

反応式

HRID 473190 の反応式
[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:40][C:41]1[NH:45][N:44]=[C:43]([NH2:46])[CH:42]=1>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11]([NH:46][C:43]2[CH:42]=[C:41]([CH3:40])[NH:45][N:44]=2)[C:10]2[C:5](=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1

参加物

7

反応物 4

HCID 24613Phosphorus oxybromideHCID 81531DiisopropylethylamineHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 178504689HCID 178504689、化合物

生成物 1

HCID 568487562-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-(methylsulfonyl)quinazolin-4-amine収率 69%

試薬・触媒・溶媒 2

HCID 1140Toluene溶媒HCID 6228Dimethylformamide溶媒

反応条件

温度
100 °C

実験手順

To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(methylsulfonyl)quinazolin-4-ol (100 mg, 0.27 mmol) were added phosphoryl tribromide (1.25 g) and toluene (0.5 mL) and DIEA (0.094 mL, 0.54 mmol), and the mixture was heated at 100° C. for 20 min. The mixture was cooled and partitioned between EtOAc and saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (67 mg, 0.69 mmol) in DMF (3 mL) and the mixture was stirred at rt for 0.5 h. The crude mixture was purified by preparative HPLC (Phenomenex C-18 reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-(methylsulfonyl)quinazolin-4-amine (72 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.21 (s, 3H) 3.47 (s, 3H) 6.14 (s, 1H) 7.83 (t, J=7.91 Hz, 1H) 7.97-8.09 (m, 2H) 8.44 (d, J=7.35 Hz, 1H) 8.68 (s, 1H) 9.03 (d, J=8.10 Hz, 1H) 11.11 (s, 1H) 12.24-12.36 (m, 1H); LC-MS (ESI) m/z 449 (M+H)+.

後処理

  1. temperatureThe mixture was cooled
  2. custompartitioned between EtOAc and saturated aq sodium bicarbonate
  3. dry with materialThe organic layer was dried over sodium sulfate
  4. concentrationconcentrated under reduced pressure
  5. customThe crude mixture was purified by preparative HPLC (Phenomenex C-18 reverse phase column
  6. washeluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O)

出典と根拠

ORDレコード
ord-4279562a1f4a4fc3b342d490087951c9
出典データセット
uspto-grants-2014_01
特許番号
US08633207B2

反応ノート

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