| 摘要 |
Disclosed is a process for the preparation of crystalline Sorafenib (4-{ 4-[({ [4-chloro-3-(trifluoromethyl)-phenyl]amino} carbonyl)amino]phenoxy} -N-methylpyridine-2-carboxamide)) free base- Form-SSB, characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 2&thetas;°peaks selected from the XRPD peak set of 9.9, 11.4, 12.6, 14.6, 15.2, 15.6, 18.1,18.6, 21.8, 22.5, 22.9, 23.6, 24.8, 25.2 ± 0.202&thetas;° comprising reacting 4-(4-aminophenoxy)-N-methyl picolinamide (III) with 4-chloro-3-(trifluoromethyl)phenylisocyanate (IV) in a high boiling organic solvent selected from methyl ethyl ketone (MEK) or methyl isobutyl ketone (MIBK) or mixtures thereof, at a temperature ranging between 75-90 °C, to yield crystalline Sorafenib base- Form-SSB. Also disclosed is a pharmaceutical composition comprising crystalline Sorafenib base- Form-SSB, together with one or more pharmaceutically acceptable excipients, wherein crystalline Sorafenib base - Form-SSB is characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 2&thetas;°peaks selected from the XRPD peak set of 9.9, 11.4, 12.6, 14.6, 15.2, 15.6, 18.1, 18.6, 21.8, 22.5, 22.9, 23.6, 24.8, 25.2 ± 0.20 2&thetas;° and DSC isotherm performed at heating rate of 10°C/min comprising a single endothermic peak having an onset at 205.1°C and a peak melting point of 207.7°C. Further disclosed is a process for the preparation of Sorafenib tosylate Form-I characterized by X-ray powder diffraction pattern comprising characteristic 2&thetas;°peaks of 4.4, 13.1. 14.7, 16.6, 17.8, 20.4, 20.7, 21.4, 22.8± 0.20 2&thetas;°, using crystalline Sorafenib base- Form-SSB, comprising steps of: a) reacting 4-(4-aminophenoxy)-N-methylpicolinamide (III) with 4-chloro-3-(trifluoromethyl)phenylisocyanate (IV) in a high boiling organic solvent selected from methyl ethyl ketone (MEK) or methyl isobutyl ketone (MIBK) or mixtures thereof; at a temperature ranging between 75-90 °C, to yield crystalline Sorafenib base (II)- Form-SSB; and b) combining crystalline Sorafenib base - Form-SSB with p-toluenesulfonic acid in the presence of methyl ethyl ketone at a temperature below 35°C, to give Sorafenib tosylate (I). |
