[NH2:1]C1C=CC(C2C3C(=NC=NC=3N)N(C3CCN(C4CCN(C)CC4)CC3)N=2)=CC=1[O:31]C.[O:33]1[C:37]([C:38](Cl)=[O:39])=[CH:36][C:35]2[CH:41]=[CH:42][CH:43]=[CH:44][C:34]1=2.[OH-].[Na+]>N1C=CC=CC=1.ClCCl>[OH-:31].[NH4+:1].[O:33]1[C:37]([C:38]([NH2:1])=[O:39])=[CH:36][C:35]2[CH:41]=[CH:42][CH:43]=[CH:44][C:34]1=2A solution of 3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.500 g, 1.15 mmol) in pyridine (8 mL) at −5° C. was treated with a solution of benzo[b]furan-2-carbonyl chloride (0.415 g, 2.3 mmol) in dichloromethane (3 mL). The reaction mixture stirred for 20 min at −5° C., then the dry ice/acetone bath was removed and was stirred at room temperature under a nitrogen atmosphere. Benzo[b]furan-2-carbonyl chloride (0.207 g, 1.15 mmol) was added to the reaction mixture and was stirred for 2 h. Sodium hydroxide (1 N) solution (10 mL) was added and was stirred over night. The organic solvent was removed under reduced pressure, and dichloromethane (20 mL) was added. The layers were partitioned, and the aqueous layer was extracted with dichloromethane (125 mL). The combined organic layers were washed with water, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl))-benzo[b]furan-2-carboxamide was purified by flash chromatography on silica gel using 15% (methanol with 2% ammonium hydroxide) in dichloromethane (10 min), 20% (methanol with 2% ammonium hydroxide) in dichloromethane (15 min), 50% (methanol with 2% ammonium hydroxide) in dichloromethane (7 min) to give 0.143 g (21%) pure N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl))-benzo[b]furan-2-carboxamide. A warmed solution of N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl))-benzo[b]furan-2-carboxamide (0.143 g, 0.246 mmol) in ethyl acetate was treated with a warmed solution of maleic acid (0.086 g, 0.739) in ethyl acetate. The precipitate was filtered under nitrogen and dried on lyophilizer to give N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-benzo[b]furan-2-carboxamide tri-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 9.518 (s, 1H), 8.282 (s, 1H), 8.2652-8.2447 (d, 1H, J=8.2 Hz), 7.849-7.814 (m, 2H), 7.7813-7.7603 (d, 1H, J=8.4 Hz), 7.562-7.523 (m, 1H), 7.418-7.369 (m, 2H), 7.338-7.313 (m, 1H), 6.088 (s, 5H), 5.10-5.00 (m, 1H), 4.003 (s, 3H), 3.529 (m, 4H), 3.314 (m, 2H), 2.971 (m, 2H), 2.778 (s, 3H), 2.497 (m, 3H), 2.209 (m, 4H), 1.909 (m, 2H); HPLC Perkin Elmer Pecosphere C18, 3 μM, 33×4.6, 3.5 ml/min 100-100% 50 mM ammonium acetate to acetonitrile in 4.5 minutes, C36H44N6O3 (581.2), 95%. LCMS (Perkin Elmer, Pecosphere C18 column, 3 um particle size, 33×4.6 mm; 100% 50 mM ammonium Acetate in Water to 100% Acetonitrile over 5 min, 3.0 to 3.5 mil/min) Rt 2.73 min (100%).
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