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

HRID 473218ノート

反応式

HRID 473218 の反応式
[CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:10]=[C:9]3O)[CH2:3][CH2:2]1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:39][C:40]1[NH:44][N:43]=[C:42]([NH2:45])[CH:41]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:10]=[C:9]3[NH:45][C:42]2[CH:41]=[C:40]([CH3:39])[NH:44][N:43]=2)[CH2:3][CH2:2]1

参加物

7

反応物 4

HCID 24613Phosphorus oxybromideHCID 81531DiisopropylethylamineHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 178517773HCID 178517773、化合物

生成物 1

HCID 568488708-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine収率 48.7%

試薬・触媒・溶媒 2

HCID 1140Toluene溶媒HCID 6228Dimethylformamide溶媒

反応条件

温度
95 °C

実験手順

To 8-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol (50 mg, 0.15 mmol) were added phosphoryl tribromide (0.86 g) and toluene (2 mL) followed by DIEA (0.053 mL, 0.3 mmol). The mixture was heated at 95° C. for 0.5 h. The mixture was cooled and partitioned between EtOAc and a saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (100 mg, 1 mmol) in DMF (3 mL) and the mixture was stirred at rt overnight. The mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 8-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (30 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79-0.90 (m, 2H) 1.04-1.16 (m, 2H) 2.17 (s, 3H) 2.95-3.10 (m, 1H) 5.97 (s, 1H) 7.32 (d, J=7.35 Hz, 1H) 7.52 (t, J=7.91 Hz, 1H) 7.96-8.06 (m, 2H) 8.43 (d, J=8.10 Hz, 1H) 8.67 (s, 1H) 10.57 (br s, 1H) 12.15 (br s, 1H); LC-MS (ESI) m/z 411 (M+H)+.

後処理

  1. temperatureThe mixture was cooled
  2. custompartitioned between EtOAc
  3. dry with materialThe organic layer was dried over sodium sulfate
  4. concentrationconcentrated
  5. customThe mixture was purified by preparative HPLC (Varian diphenyl 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-41dda6787df24cf7b4bc22b533ce10b3
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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