Patent ID: 8530701

Claim:
A process for producing a 2-[4-(3- or 2-fluorobenzyloxy)benzylamino]propanamide compound selected from (S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide (safinamide) of formula (Ia), (S)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (ralfinamide) of formula (Ib), the respective R-enantiomers (I′a) and (I′b), the respective racemic mixtures (Ia, I′a) and (Ib, I′b) and the salts thereof with pharmaceutically acceptable acids, wherein safinamide (Ia), ralfinamide (Ib), the respective R-enantiomer (I′a) or (I′b), or the respective racemic mixture (Ia, I′a) and (Ib, I′b) or a salt thereof with a pharmaceutically acceptable acid has a content of the respective impurity, (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide (IIa), (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide (IIb), the respective R-enantiomer (II′a) or (II′b), or the respective racemic mixture (IIa, II′a) or (IIb, II′b) or a salt thereof with a pharmaceutically acceptable acid, which is lower than 0.03% by weight, characterized in that a Schiff base intermediate of formula (IIa), (IIIb) the respective R-enantiomer (III′a) or (III′b) or the respective racemic mixture (IIIa, III′a) or (IIIb, III′b) (i) is obtained by an iminoalkylation reaction of 4-(3- or 2-fluorobenzyloxy)benzaldehyde with L-alaninamide or D-alaninamide or the racemic mixture thereof, without any addition of molecular sieves, in a solvent selected from (C 1 -C 5 ) lower alkanols at a temperature between 20° and 30° C. in an amount of such solvent with respect to the aldehyde which allows formation of a suspension of the Schiff base in a saturated solution of the Schiff base in the same solvent, and (ii) after completion of the iminoalkylation reaction, is submitted to a reduction reaction with a reducing agent selected from sodium borohydride and potassium borohydride in an organic solvent selected from one or more (C 1 -C 5 ) lower alkanols, optionally with water, wherein the ratio of the organic solvent to the Schiff base allows the formation and the presence during a substantial portion of the reduction reaction course of a suspension of the Schiff base into the saturated solution of the Schiff base in the same organic solvent and ranges from 0.5 L to 3.0 L per each mole of Schiff base, (iii) the process being further characterized in that the 4-(3- or 2-fluorobenzyloxy)benzaldehyde starting material employed for the preparation of the Schiff base intermediate (IIIa), (IIIb), (III′a), (III′b) or the respective racemic mixture (IIIa, III′a) or (IIIb, III′b) has a content of 3-(3- or 2-fluorobenzyl)-4-(3- or 2-fluorobenzyloxy)benzaldehyde impurity lower than 0.03% by weight; whereby safinamide (Ia), ralfinamide (Ib), the respective R-enantiomer (I′a) or (I′b) or the respective racemic mixture (Ia, I′a) or (Ib, I′b) is obtained in a free base form and optionally, said free base form is converted to a salt thereof with a pharmaceutically acceptable acid.