Pyridine → 4-{2-[Bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenyl]-amide

HRID 912158

反応式

HRID 912158 の反応式
[CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.ClC(Cl)(O[C:51](=[O:57])OC(Cl)(Cl)Cl)Cl.[CH2:59]([N:61]1[CH2:66][CH2:65][N:64]([C:67]2[CH:72]=[C:71]([F:73])[C:70]([NH2:74])=[C:69]([F:75])[CH:68]=2)[CH2:63][CH2:62]1)[CH3:60]>ClCCl>[CH2:59]([N:61]1[CH2:66][CH2:65][N:64]([C:67]2[CH:68]=[C:69]([F:75])[C:70]([NH:74][C:51]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)=[O:57])=[C:71]([F:73])[CH:72]=2)[CH2:63][CH2:62]1)[CH3:60]

参加物

6

反応物 4

HCID 1049PyridineHCID 94429TriphosgeneHCID 45258862Bis-(4-methoxybenzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amineHCID 592443794-(4-Ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine

生成物 1

HCID 673862134-{2-[Bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenyl]-amide

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒5 回

反応条件

温度
0 °C

実験手順

To a solution of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (2.48 g, 4.59 mmol) in dichloromethane (50 ml), pyridine (743 μl, 9.19 mmol) was added, followed by cooling to 0° C. To this, triphosgene (2.73 g, 9.19 mmol) was added, which was raised to room temperature, followed by stirring for 1 hour. The solvent was distilled off under reduced pressure, and dissolved again in dichloromethane (50 ml), to which a solution of 4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine (1.33 g, 5.51 mmol) obtained in Step C in dichloromethane (50 ml) was added dropwise over 30 minutes, followed by stirring for 1 hour. Dichloromethane (100 ml) was added, followed by further stirring at room temperature for 19 hours. 100 ml of Dichloromethane was added, followed by adsorption to silica gel, and subsequently the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=50/1 to 10/1), to obtain 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenyl]-amide as a crude product. This was dissolved in TFA (45 ml), and N-acetylcysteine (1.49 g, 9.15 mmol) was added, followed by refluxing for 6 hours. After the solvent was distilled off under reduced pressure, 5M-NaOH aqueous solution was added to adjust the pH to 8, and the resulting solid was washed with aqueous sodium bicarbonate (50 ml), water (50 ml) and methanol (50 ml), followed by purification by silica gel column chromatography (dichloromethane/methanol=100/1 to 10/1), to obtain the desired compound as a colorless solid (1.34 g, 52%).

後処理

  1. temperaturewhich was raised to room temperature
  2. distillationThe solvent was distilled off under reduced pressure
  3. additionwas added dropwise over 30 minutes
  4. stirringby stirring for 1 hour
  5. stirringby further stirring at room temperature for 19 hours
  6. distillationsubsequently the solvent was distilled off under reduced pressure
  7. customThis was purified by silica gel column chromatography (dichloromethane/methanol=50/1 to 10/1)

出典と根拠

ORDレコード
ord-cb7fa76bce5c46a1afb14cce8ef95ed1
出典データセット
uspto-grants-2011_09
特許番号
US08022205B2

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