摘要 |
The invention concerns a process for preparing olopatadine or a salt thereof, comprising:. (a) reacting 11-oxo-6,11-dihydroxydibenz[b,e]oxepin-2-acetic acid, a Wittig reagent selected from the group consisting of 3-dimethylamino-propyltriphenylphosphonium halides and salts thereof, and a suitable base, under Wittig 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, 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]- 6,1 l-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 pH 4 and pH 5 to provide acid-addition salts of olopatadine and (E)-11-[3-dimethylaminopropylidene]- 6,1 l-dihydrodibenz[b,e]oxepin-2-acetic acid; (f) extracting the acid-addition salts of olopatadine and (E)-11-[3- dimethylaminopropylidene]-6,l l-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 Cl - 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; and (h) fractionnally crystallizing the acid-addition salt of olopatadine. |
申请人 |
AZAD PHARMACEUTICAL INGREDIENTS, AG.;BADER, THOMAS;BICHSEL, HANS-ULRICH;GILOMEN, BRUNO;MEYER-WILMES, IMELDA;SUNDERMEIER, MARK |
发明人 |
BADER, THOMAS;BICHSEL, HANS-ULRICH;GILOMEN, BRUNO;MEYER-WILMES, IMELDA;SUNDERMEIER, MARK |