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

Reaktionsgleichung

[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]

Komponenten

Reaktionsbedingungen

Temperatur: 0 °C

Versuchsvorschrift

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%).

Aufarbeitung

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

Quellen und Nachweise

ORD-Eintrag: ord-cb7fa76bce5c46a1afb14cce8ef95ed1
Quelldatensatz: uspto-grants-2011_09
DOI: 10.6084/m9.figshare.5104873.v1
Patentnummer: US08022205B2

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