ISOLATED ATOMOXETINE IMPURITY, PROCEDURE FOR THE PREPARATION OF ATOMOXETINE IMPURITIES AND ITS USE AS REFERENCE PATTERNS.

摘要

N-methyl-3- (3-methylphenoxy) -3-phenylpropylamine (3-ATM HCl) hydrochloride isolated. Process for the preparation of N-methyl-3- (3-methylphenoxy) -3-phenylpropylamine hydrochloride (3-ATM HCl) comprising: (a) combining N-methyl-3-hydroxy-3-phenylpropylamine with DMSO in presence of a strong base selected from NaOH, KOH, Ca (OH) 2 and Ba (OH) 2 at a temperature of at least 90 ° C to form a mixture; (b) add 3-fluorotoluene to the mixture formed in (a), to form a reaction mixture, and maintain the reaction mixture for at least 5 hours; (c) add a first organic solvent and water to the reaction mixture; (d) recover the crude base (ñ) 3-methyl tomoxetine; (e) combine the crude base (ñ) 3-methyl tomoxetine with the (S) - (+) - mandelic acid in the presence of a C1-4 alcohol and an aromatic solvent, and heat at a temperature of 65 ° C to 70 ° C; (f) recover the salt (S) - (+) - 3-methyl atomoxetine mandelate; (g) combine the salt (S) - (+) - 3-methyl atomoxetine mandelate with a second organic solvent, water and a base; (h) recover the base of 3-methyl atomoxetine; and (i) convert the recovered 3-methylatomoxetine base into its hydrochloride salt.