Reaktion #519485

Reaktionsgleichung

sodium hydroxide

cis-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol

2-fluoro-6-(2-pyridylsulfanyl)benzonitrile

potassium carbonate

→

cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-(2-pyridylsulfanyl)benzonitrile

Ausbeute 68.2%

Lösungsmittel

Ethyl acetate

dimethylformamide

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe layers were partitioned
2. 2
   Waschenthe organic layer was washed with 1 N sodium hydroxide solution (300 mL)
3. 3
   WaschenThe organic layer was washed with water and brine (250 mL each)
4. 4
   Trocknendried over magnesium sulfate
5. 5
   Filtrationfiltered
6. 6
   Sonstigeevaporated under reduced pressure
7. 7
   SonstigeThe solid was triturated with ethyl acetate

Vorschrift

A solution of cis-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol (0.300 g, 0.736 mmol) in dimethylformamide (20 mL), was treated with 2-fluoro-6-(2-pyridylsulfanyl)benzonitrile (0.424 g, 1.84 mmol) and potassium carbonate (0.203, 1.47 mmol). The reaction mixture was stirred at 120° C. for 2 h under a nitrogen atmosphere. Ethyl acetate (125 mL) and 1 N sodium hydroxide solution (50 mL) were added to the reaction mixture. The layers were partitioned and the organic layer was washed with 1 N sodium hydroxide solution (300 mL). The organic layer was washed with water and brine (250 mL each), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The solid was triturated with ethyl acetate to yield 0.310 g (68%) of cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-(2-pyridylsulfanyl)benzonitrile. A warm solution of cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-(2-pyridylsulfanyl)benzonitrile (0.310 g, 0.502 mmol) in ethanol was treated with a warm solution maleic acid (0.175 g, 1.503 mmol) in ethanol. A precipitate formed upon cooling and was filtered under a nitrogen atmosphere to give 0.356 g of cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-(2-pyridylsulfanyl)benzonitrile bis-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 8.47-8.46 (d, 1H, J=4 Hz), 8.26 (s, 1H), 7.79-7.72 (m, 4H), 7.53-7.51 (d, 1H, J=8 Hz), 7.38-7.34 (m, 3H), 7.28-7.24 (m, 2H), 6.14 (s, 4H), 4.85 (m, 1H), 3.60-3.10 (m, 7H), 3.1-2.85 (m, 2H), 2.71-2.67 (m, 2H), 2.32-2.27 (m, 3H), 2.05-1.99 (m, 2H), 1.78-1.71 (m, 4H); 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 5.196 min (98%).

Quelle