1,4-Dioxane → 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

HRID 1910010ノート

反応式

HRID 1910010 の反応式
I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[CH2:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].C(=O)(O)[O-].[Na+].O1CCOCC1>O>[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[CH2:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=3)=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)=[O:25]

参加物

6

反応物 4

HCID 312751,4-DioxaneHCID 516892Sodium BicarbonateHCID 249053373-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amineHCID 668235701-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole

生成物 1

HCID 668238873-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

試薬・触媒・溶媒 1

HCID 962Water溶媒

反応条件

温度
120 °C

実験手順

To a 25 mL pressure tube was charged 3-iodo-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (70.9 mg, 0.234 mmol), 1-[(2,5-difluorophenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (93 mg, 0.234 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (9.55 mg, 0.012 mmol), and sodium bicarbonate (39.3 mg, 0.468 mmol) followed by dioxane (4 mL), and water (1 mL). The reaction was heated at 120° C. for 40 min in microwave reactor. LCMS showed incomplete conversion. The reaction was heated in microwave at 120° C. for another 1 hour. The reaction was cooled to room temperature, the mixture was transferred into a 100 mL erlenmeyer flask, rinsed by EtOAc, with the water layer and black greasy solid stayed in tube (total 100 mL of EtOAc was added to the mixture). The EtOAc solution was evaporated to dryness, and re-dissolved in CH2Cl2/MeOH (8 mL/2 mL). It was purified by flash column 25-100% EtOAc/hexane, then 0-10% MeOH/EtOAc, Analogix Si SF15-24g, to afford a brown solid. The brown solid was further purified by recrystallization from CH3CN to give the title compound as a brown solid. LC/MS (ES) m/z=449.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49 (d, J=6.82 Hz, 6H), 3.27-3.33 (m, 2H), 3.97 (s, 2H), 4.31 (t, J=8.46 Hz, 2H), 5.06 (t, J=6.82 Hz, 1H), 7.18-7.21 (m, 1H), 7.22-7.27 (m, 2H), 7.44 (d, J=8.08 Hz, 1H), 7.54 (s, 1H), 8.15 (d, J=8.34 Hz, 1H), 8.23 (s, 1H).

後処理

  1. temperatureThe reaction was heated in microwave at 120° C. for another 1 hour
  2. temperatureThe reaction was cooled to room temperature
  3. customthe mixture was transferred into a 100 mL erlenmeyer flask
  4. washrinsed by EtOAc, with the water layer and black greasy solid
  5. customstayed in tube
  6. addition(total 100 mL of EtOAc was added to the mixture)
  7. customThe EtOAc solution was evaporated to dryness
  8. dissolutionre-dissolved in CH2Cl2/MeOH (8 mL/2 mL)
  9. customIt was purified by flash column 25-100% EtOAc/hexane
  10. custom0-10% MeOH/EtOAc, Analogix Si SF15-24g, to afford a brown solid
  11. customThe brown solid was further purified by recrystallization from CH3CN

出典と根拠

ORDレコード
ord-b8112b8a9a9b4e9b955d2b76b87c3e42
出典データセット
uspto-grants-2013_12
特許番号
US08598156B2

反応ノート

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