Dimethylformamide → HCID 178495259, Verbindung

HRID 432307Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 432307
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.F[C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH2:41][CH2:42]OC)[C:33]=1[C:34]#[N:35].[C:45](=[O:48])([O-])[O-].[K+].[K+].[OH-].[Na+].[CH3:53]N(C)C=O>C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:32]4[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][CH2:41][CH2:42][CH2:53][O:48][CH3:45])[C:33]=4[C:34]#[N:35])=[CH:13][CH:12]=3)[C:3]=12

Komponenten

7

Edukt 5

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 223466972-Fluoro-6-[(2-methoxyethyl)amino]benzonitrileHCID 178481007HCID 178481007, Verbindung

Produkt 1

HCID 178495259HCID 178495259, VerbindungAusbeute 48 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

A solution of trans-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol (0.100 g, 0.245 mmol) in dimethylformamide (25 mL), was treated with 2-fluoro-6-[(2-methoxyethyl)amino]benzonitrile (0.128 g, 0.613 mmol) and potassium carbonate (0.068, 0.49 mmol). The reaction mixture was stirred at 120° C. over night under a nitrogen atmosphere. Ethyl acetate and 1 N sodium hydroxide solution were added to the reaction mixture. The organic layer was washed with 1 N sodium hydroxide solution (1 L). The layers were partitioned and the organic layer was washed with water and brine (500 mL each), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 10% methanol in dichloromethane as eluent, to afford 71 mg (48%) of trans-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(3-methoxypropyl)amino]benzonitrile. A warm solution of trans-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(3-methoxypropyl)amino]benzonitrile (0.071 g, 0.119 mmol) in ethyl acetate was treated with a warm solution of maleic acid (0.042 g, 0.358 mmol) in ethyl acetate. The precipitate was filtered under nitrogen and dried under high vacuum to give trans-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(3-methoxypropyl)amino]benzonitrile tris-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 8.23 (s, 1H), 7.69-7.67 (d, 2H, J=8 Hz), 7.37-7.33 (m, 1H), 7.25-7.23 (d, 2H, J=8 Hz), 6.53-6.51 (d, 1H, J=8 Hz), 6.30-6.29 (m, 1H), 6.19-6.17 (d, 1H, J=8 Hz), 6.17 (s, 6H), 4.65-4.64 (m, 1H), 3.45-3.42 (m, 2H), 3.27 (s, 3H), 2.55-2.50 (m, 4H), 2.50-2.30 (m, 5H), 2.33 (br, s, 3H), 2.01-1.96 (m, 8 Hz), 1.84-1.80 (m, 2H), 1.49-1.46 (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 5.181 min (95%).

Aufarbeitung

  1. washThe organic layer was washed with 1 N sodium hydroxide solution (1 L)
  2. customThe layers were partitioned
  3. washthe organic layer was washed with water and brine (500 mL each)
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. customevaporated under reduced pressure
  7. customThe crude product was purified by flash chromatography on silica gel using 10% methanol in dichloromethane as eluent

Quellen und Nachweise

ORD-Eintrag
ord-32cf68f3ced14eb8b572d432a8eff052
Quelldatensatz
uspto-grants-2003_12
Patentnummer
US06660744B1

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