POLYMORPHIC FORMS OF OLOPATADINE HYDROCHLORIDE AND METHODS FOR PRODUCING OLOPATADINE AND SALTS THEREOF

摘要

, (a) reacting 11-oxo-6,11-dihydroxydibenz [b,e] oxepin-2-acetic acid, a Witting reagent selected from the group consisting of 3-dimethylamino-propylt-riphenylphosphonium halides and salts thereof, and a suitable base, under Witting reaction conditions, to provide a reaction mixture containing olopatadine; (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, or the pH of the hydrolyzed reaction mixture, aqueous phase thereof, to a pH of about pH 12 or higher to convert excess 3-dimethylamino-propyldiphenyphosphonium 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 cliastereomeric 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 pH4 and pH5 to provide acid-addition salts of olopatadine and (E)-11-[3-dimethylaminopropy-lidene]-6,11- dihydrodibenz [b,e] oxepin-2-acetic; (f) extracting the acid-addition salts of olopatadine and (E)-11-[3-dimethylaminopropylidene]- 6,11-dihydrodibenz [b,e] oxepin-2-acetic with a water-miscible 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-butano1/water; (g) concentrating by azeotropic distillation the n-butano1/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.