Process for the production of 2-[4-(3- and 2-fluorobenzyloxy) benzylamino] propanamides
AssigneeNewron Pharmaceuticals S.p.A.
InventorsElena Barbanti, Carla Caccia, Patricia Salvati, Francesco Velardi, Tiziano Ruffilli, Luigi Bogogna
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Abstract
A process for obtaining therapeutically active 2-[4-(3- and 2-(fluorobenzyloxy)benzylamino]propanamides and their salts with pharmaceutically acceptable acids with high purity degree, in particular, with a content of dibenzyl derivatives impurities lower than 0.03%, preferably lower than 0.01% by weight. The process is carried out by submitting the Schiff bases intermediates 2-[4-(3- and 2-fluorobenzyloxy)benzylideneamino]propanamides to catalytic hydrogenation in the presence of a heterogeneous catalyst in a protic organic solvent.
Claims58
A process for producing high purity (S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide (safinamide) or (S)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (ralfinamide) of formula (Ia) or (Ib)
- and pharmaceutically acceptable acid salts thereof, comprising:
- submitting a Schiff base intermediate respectively of formula (VIa) or (VIb)
- to catalytic hydrogenation with hydrogen gas in the presence of a heterogeneous catalyst in a protic organic solvent and, when safinamide or ralfinamide are obtained in a free base form, optionally converting said free base form to a salt thereof with a pharmaceutically acceptable acid.
An isolated Schiff base of formula (VIa) or (VIb)
High purity safinamide or ralfinamide or a pharmaceutically acceptable acid salt thereof with a content of the respective impurity (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide (IIa) or (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide (IIb)
- or their pharmaceutically acceptable acid salts, which is lower than 0.03% (by weight).
A method for treating CNS disorders, selected from the group consisting of epilepsy, Parkinson disease, Alzheimer disease, depression, restless legs syndrome and migraine comprising administering to a patient in need thereof an effective amount of high purity safinamide or a pharmaceutically acceptable acid salt thereof wherein the content of the impurity (S)-2-[3-(3-fluorobenzyloxy)-4-(3-fluorobenzyl)-benzylamino]propanamide of formula (IIa)
- or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).
A method for treating pain conditions, migraine, bipolar disorders, depressions, cardiovascular, inflammatory, urogenital, metabolic and gastrointestinal disorders comprising administering to a patient in need thereof an effective amount of high purity ralfinamide or a salt thereof with a pharmaceutically acceptable acid wherein the content of the impurity 2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide of formula (IIb)
- or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).
Dependencies are inferred from the claim text.