Patent ID: 7687646
Filing Date: 2010-03-30
Classification: A61P,C07D,C07F

Abstract:
1. A process for preparing olopatadine or a salt thereof, comprising: (a) reacting in a suitable solvent 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, a Wittig reagent selected from the group consisting of 3-dimethylamino-propyltriphenylphosphonium halides and salts thereof, and a base selected from the group consisting of sodium hydride, (C (b) adding an amount of water sufficient to protonate residual ylide present in the reaction mixture to provide a hydrolyzed reaction mixture; (c) adjusting, if necessary, the pH of the hydrolyzed reaction mixture, or aqueous phase thereof, to a pH of about pH 12 or higher to convert excess 3-dimethylamino -propyltriphenylphosphonium halide, or salt thereof, into 3-dimethylamino-propyldiphenylphosphine oxide; (d) extracting the solution of step (c) with a suitable solvent to provide a solution containing a diastereomeric mixture of olopatadine and (E)-11-[3-dimethylaminopropylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid and having a substantially reduced amount of 3-dimethylamino-propyldiphenylphosphine oxide; (e) adjusting the pH of the solution obtained in step (d) to a pH between about pH 4 and pH 5 to provide acid-addition salts of olopatadine and (E)-11-[3-dimethylaminopropylidene]-6,11-dihydrodibenzl[b,e]oxepin-2-acetic acid; (f) extracting the acid-addition salts of olopatadine and (E)-11-[3-dimethylaminopropylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid with a water-mixable solvent selected from the group consisting of (i) n-butanol; and (ii) mixtures of methyl-THF and a C1-C4 alcohol; provided that if the selected solvent is a mixture of methyl-THF and a C1-C4 alcohol, then the solution is evaporated and the residue is taken up in n-butanol/water; (g) concentrating by azeotropic distillation the n-butanol/water solvent containing the acid-addition salts of olopatadine and (E)-11-[3-dimethylaminopropylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid; (h) fractionally crystallizing the acid-addition salt of olopatadine; (i) optionally, reacting the acid-addition salt of olopatadine with a sufficient amount of a base to liberate olopatadine; and (j) optionally, reacting the olopatadine with a sufficient amount of an acid to convert the olopatadine into a salt of olopatadine.