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Potassium Carbonate → N-(3-chloro-4-fluorophenyl)-6-(3-((1R,5S)-1-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3-yl) propoxy)-7-methoxyquinazolin-4-amine

HRID 712395
ノート
印刷プレビュー

反応式

HRID 712395 の反応式
[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][C@H:37]2[C@:35]([N:39]([CH3:41])[CH3:40])([CH2:36]2)[CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][C@H:37]5[C@:35]([N:39]([CH3:41])[CH3:40])([CH2:36]5)[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
参加物反応条件実験手順後処理出典と根拠反応ノート

参加物

5

反応物 3

HCID 11430Potassium CarbonateHCID 104712174-[(3-Chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-olHCID 86729465(1R,5S)-3-(3-chloropropyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine

生成物 1

HCID 71573149N-(3-chloro-4-fluorophenyl)-6-(3-((1R,5S)-1-(dimethylamino)-3-azabicyclo[3.1.0]hexan-3-yl) propoxy)-7-methoxyquinazolin-4-amine収率 67.7%

試薬・触媒・溶媒 1

HCID 6228
Dimethylformamide
溶媒
2 回

反応条件

温度
80 °C

実験手順

To a mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (136 mg, 0.42 mmol, 1.0 eq) and anhydrous K2CO3 (290 mg, 2.10 mmol, 5.0 eq) in DMF (3 mL) was added a solution of (1R,5S)-3-(3-chloropropyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine (103 mg, 0.52 mmol, 1.2 eq) in DMF (2 mL) at room temperature. The reaction mixture was heated at 80° C. for 11 h and cooled to room temperature. Then the reaction mixture was quenched with water (5 mL) and diluted with EtOAc (10 mL). The organic phase was separated from the mixture, and the water phase was extracted with EtOAc (5 mL×3). The combined organic phases were, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (10:1 (v/v)CH2Cl2/CH3OH) to give the crude product, which was then recrystallized from CH2Cl2/PE to afford title compound as a yellow solid (138 mg, 67.7%), HPLC: 96.5%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 0.81 (1H, m), 1.11 (1H, m), 1.26 (1H, br s), 1.52 (1H, m), 2.38 (6H, s), 2.65-2.81 (3H, m), 3.11 (2H, m), 3.42 (1H, br s), 3.98 (3H, s), 4.18 (2H, t, J=6.8 Hz), 7.14 (1H, t, J=8.8 Hz), 7.25 (1H, d, J=14.4 Hz), 7.41 (1H, s), 7.66 (1H, m), 7.98 (1H, dd, J=5.2, 6.8 Hz), 8.64 (1H, s) ppm.

後処理

  1. temperaturecooled to room temperature
  2. customThen the reaction mixture was quenched with water (5 mL)
  3. additiondiluted with EtOAc (10 mL)
  4. customThe organic phase was separated from the mixture
  5. extractionthe water phase was extracted with EtOAc (5 mL×3)
  6. dry with materialdried over anhydrous Na2SO4
  7. filtrationfiltered
  8. concentrationThe filtrate was concentrated in vacuo
  9. customthe residue was purified by a silica gel column chromatography (10:1 (v/v)CH2Cl2/CH3OH)
  10. customto give the crude product, which
  11. customwas then recrystallized from CH2Cl2/PE

出典と根拠

ORDレコード
ord-b23cdb76f94f43f0be142b097ebff072
出典データセット
uspto-grants-2015_11
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US09181277B2

反応ノート

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このページの内容参加物反応条件実験手順後処理出典と根拠反応ノート