反应详情

Tetrakis(triphenylphosphine)palladium (0.035 g, 0.03 mmol) was added and the mixture stirred over night (15 h). The organic layer was removed under reduced pressure, and ethyl acetate was added. The layers were partitioned, and the aqueous layer was extracted with ethyl acetate (300 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel, using 10% methanol in dichloromethane (6 L) as eluent. A second purification on a Supelco flash chromatography column was required, using 20% methanol in dichloromethane as eluent. The second column afforded 0.132 g (38%) of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide. The product was sent for preparative HPLC purification (Hypersil C18, 100×21 mm column, 5 μm, 15-100% Acetonitrile gradient over 8 min, total run time—10 min, buffer—50 mM Ammonium Acetate, 25 ml/min), and afforded 0.026 g of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide. A warm solution of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide (0.026 g, 0.046 mmol) in ethyl acetate was treated with a warm solution of maleic acid (0.016 g, 0.137 mmol) in ethyl acetate. The precipitate was filtered under nitrogen atmosphere and dried under high vacuum to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide tris-maleate.

1. filtrationThe precipitate was filtered under nitrogen atmosphere
2. customdried under high vacuum