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Dissolve 4- {4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-l -methyl- lH-imidazol-2- yl]-piperidin-l-yl}-lH-pyrazolo[3,4-2O:acetone mixture (360 mL). Add a solution of p-toluenesulfonic acid monohydrate (10.25g, 53.9 mmoles, 1.2 eq) in a 20: 1 H2ψ:acetone mixture (40 mL) to the reaction over 20 minutes at 20 0C. Heat the reaction mixture to 55 0C, hold for 1 hour, then cool to 25 0C over 1 hour. Filter the solid and wash the cake with water (40 mL). Drying under vacuum at 50 0C affords 4-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-l-methyl-lH- imidazol-2-yl]-piperidin-l-yl}-lH-pyrazolo[3,4-(i]pyrimidine p-toluenesulfonate (23.9g, 86percent) as a white solid.
57
Dissolve 4- {4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-l -methyl- lH-imidazol-2- yl]-piperidin-l-yl}-lH-pyrazolo[3,4-2O:acetone mixture (360 mL). Add a solution of p-toluenesulfonic acid monohydrate (10.25g, 53.9 mmoles, 1.2 eq) in a 20: 1 H2θ:acetone mixture (40 mL) to the reaction over 20 minutes at 20 0C. Heat the reaction mixture to 55 0C, hold for 1 hour, then cool to 25 0C over 1 hour. Filter the solid and wash the cake with water (40 mL). Drying under vacuum at 50 0C affords 4-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-l-methyl-lH- imidazol-2-yl]-piperidin-l-yl}-lH-pyrazolo[3,4-(i]pyrimidine p-toluenesulfonate (23.9g, 86%) as a white solid.
In methanol at 5℃; for 1h;
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EXAMPLE 58; Crystalline 4- {4-r4-(4-Fluoro-3-trifluoromethyl-phenyl)-l-methyl-lH-imidazol-2-yl1- piperidin- 1 -yl| - lH-pyrazoloP ,4-to 5 0C. After 1 h at 5 0C, stop stirring and filter the slurry on a Buchner funnel. Rinse the flask out with 75mL of cold 5% aq. MeOH and use this rinse to wash the filter cake. Transfer the solids to a weighing dish and dry at 50 0C in vacuo all day and all night, with a slow air bleed. The final weight is 71.44 g.X-ray powder diffraction analysis is performed with a D4 Endeaver diffractometer, equipped with a CuKa source (λ=l.54056 A) operating at 40 kV and 50 mA. The sample is scanned from 4° to 40° in 2θ, with a step size of 0.009 in 2θ and a scan rate of > 1.5 sec per step.The present invention provides crystalline 4- {4-[4-(4-Fluoro-3-trifluoromethyl- phenyl)- 1 -methyl- lH-imidazol-2-yl] -piperidin- 1 -yl} - lH-pyrazolo [3 ,4-least one peak in the x-ray pattern at 2θ diffraction angle of 13.7° +/- 0.1 or 10.3° +/- 0.1 for the manufacture of a medicament for the inhibition of angiogenesis or treatment of adenocarcinoma of the colon.