Teva Pharmaceutical Fine Chemicals S.r.l.

Teva Pharmaceutical Fine Chemicals

Eugenio Castelli

Paola Daverio

Silvia Mantovani

Stefano Bianchi

Paolo Riva

Alessandra Vailati

Giuseppe Lo Monaco

Judith Aronhime

Adrienne Kovacsne-Mezei

Stable Atomoxetine hydrochloride, a process for the manufacture thereof, the use of stable Atomoxetine Hydrochloride for making a pharmaceutical formulation, a process for the preparation of any form of Atomoxetine Hydrochloride, and an analytical method for analyzing the stability of Atomoxetine Hydrochloride are provided.

Stable atomoxetine hydrochloride, a process for the preparation thereof, and an analytical control of its stability

The present invention provides improved processes for the preparation of atomoxetine hydrochloride under reaction conditions that improve reaction yields and facilitate commercial synthesis. In particular, the invention is directed to the synthesis of atomoxetine HCl by adding HCl to a mixture of (R)-(&#x2212;)-tomoxetine (S)-(+)-mandelate with an organic solvent, with or without a base and water.

Process for the preparation of atomoxetine hydrochloride

The present invention provides novel crystalline polymorph forms of atomoxetine hydrochloride denominated Forms B and C and methods for their preparation, as well as methods for the preparation of Form A. The present invention provides pharmaceutical compositions that comprise atomoxetine hydrochloride Form B, Form C, or mixtures thereof that can be used to treat attention deficit/hyperactivity disorder.

Polymorphs of atomoxetine hydrochloride

The present invention provides enantiomerically pure (R)-(&#x2212;)-tomoxetine (S)-(+)-mandelate and atomoxetine HCl. The present invention further provides enantiomerically pure (R)-(&#x2212;)-tomoxetine (S)-(+)-mandelate prepared from racemic tomoxetine. The present invention also provides enantiomerically pure atomoxetine HCl prepared from (R)-(&#x2212;)-tomoxetine (S)-(+)-mandelate.

Enantiomerically pure atomoxetine and tomoxetine mandelate

The present invention provides improved processes for the preparation of atomoxetine hydrochloride under reaction conditions that improve reaction yields and facilitate commercial synthesis. In particular, the invention is directed to the synthesis of atomoxetine HCl by adding HCl to a mixture of (R)-(&#x2212;)-tomoxetine (S)-(+)-mandelate with an organic solvent, with or without a base and water. In preferred embodiments, the atomoxetine hydrochloride produced is Form A.

Processes for the preparation of atomoxetine hydrochloride

The present invention provides isolated N-methyl-3-(3-methylphenoxy)-3-phenylpropylamine hydrochloride, and preparation thereof as well as of N-methyl-3-(4-methylphenoxy)-3-phenylpropylamine hydrochloride and of N-methyl-3-phenoxy-3-phenylpropylamine hydrochloride. The invention further provides the use of the above compounds as reference markers and/or reference standards during the synthesis of Atomoxetine. Also provided is a method of limiting the amounts of the impurities 3FT (3-fluorotoluene), 4FT (4-fluorotoluene), and FB (fluorobenzene) in the 2-fluorotoluene starting material used in the synthesis of Atomoxetine Hydrochloride. The purity of the Atomoxetine Hydrochloride product is ensured by determining the amounts of 3FT, 4FT, and FB in the 2-fluorotoluene starting material with the marker 3-ATM HCl.

Isolated atomoxetine impurity, processes for the preparation of atomoxetine impurities and their use as reference standards

Provided are processes for preparing tomoxetine comprising reacting N-methyl-3-hydroxy-3-phenylpropylamine with dimethylsulfoxide (DMSO) and 2-fluorotoluene in the presence of an alkali base to form tomoxetine. Also provided is the conversion of said tomoxetine into atomoxetine or a pharmaceutically acceptable salt thereof.

Processes for the preparation of tomoxetine

The present invention provides a process for the optical resolution of racemic tomoxetine under reaction conditions that improve reaction yields and optical purity. The invention also provides an epimerization process for the (S)-(+) enantiomer. The invention further provides the conversion of the enantiomer obtained from the optical resolution into atomoxetine or a pharmaceutically acceptable salt thereof.

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Arlate di Calco, Italy

Eugenio Castelli