4-(Dimethylamino)benzoyl chloride → N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide

HRID 432320ノート

反応式

HRID 432320 の反応式
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[CH3:33][N:34]([CH3:44])[C:35]1[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=1>N1C=CC=CC=1.ClCCl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[C:38]4[CH:37]=[CH:36][C:35]([N:34]([CH3:33])[CH3:44])=[CH:40][CH:39]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12

参加物

5

反応物 2

HCID 44007824-(Dimethylamino)benzoyl chlorideHCID 223469753-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

生成物 1

HCID 22347336N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide収率 53.3%

試薬・触媒・溶媒 2

HCID 1049Pyridine溶媒HCID 6344Dichloromethane溶媒

反応条件

温度
-5 °C

実験手順

A suspension of 3-(4-Amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.398 g, 0.912 mmol) in pyridine (7 mL) at −5° C. was treated with a solution of 4-(dimethylamino)-1-benzenecarbonyl chloride (0.167 g, 0.912 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at −5° C. for 2.5 h, and the ice bath was removed. 1 N sodium hydroxide solution (10 mL) was added to the reaction mixture and stirred for 1 h. The organic layer was removed under reduced pressure, and dichloromethane (15 mL) was added. The layers were separated using an Empore extraction cartridge. The organic layer was removed under reduced pressure. The crude solid was purified two times by flash chromatography on silica gel using 12% (methanol with 5% ammonium hydroxide) in dichloromethane as eluent to give 0.284 g (53%) of N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide. A hot solution of N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide (0.284 g, 0.487 mmol) in ethyl acetate and a few drops of ethanol was treated with a hot solution of maleic acid (0.169 g, 1.46 mmol) in ethyl acetate. The precipitate formed was filtered under nitrogen and dried under high vacuum to give 0.409 g N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide tris-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 9.054 (s, 1H), 8.278 (s, 1H), 8.215-8.194 (m, 1H), 7.851-7.828 (m, 2H), 7.312-7.308 (m, 1H), 7.288-7.263 (m, 1H), 6.794-6.772 (m, 2H), 6.096 (s, 6H), 5.10-5.00 (m, 1H), 3.951 (s, 3H), 3.538 (s, 4H), 3.061 (s, 8H), 2.215-2.183 (m, 4H), 1.90-1.81 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 4.496 min (98%).

後処理

  1. customthe ice bath was removed
  2. addition1 N sodium hydroxide solution (10 mL) was added to the reaction mixture
  3. stirringstirred for 1 h
  4. customThe organic layer was removed under reduced pressure, and dichloromethane (15 mL)
  5. additionwas added
  6. customThe layers were separated
  7. extractionan Empore extraction cartridge
  8. customThe organic layer was removed under reduced pressure
  9. customThe crude solid was purified two times by flash chromatography on silica gel using 12% (methanol with 5% ammonium hydroxide) in dichloromethane as eluent

出典と根拠

ORDレコード
ord-a820c27be8b844a3b6b35d00aa31d613
出典データセット
uspto-grants-2003_12
特許番号
US06660744B1

反応ノート

読み込み中…