High purity 2-[4-(3- OR 2-fluorobenzyloxy)benzylamino]propanamides and methods of use thereof
Inventors
Barbanti, Elena • Faravelli, Laura • Salvati, Patricia • Canevotti, Renato • Ponzini, Francesco
Assignees
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Publication Number
US-8530701-B2
Publication Date
2013-09-10
Expiration Date
Abstract
A process for obtaining therapeutically active 2-[4-(3- and 2-(fluorobenzyloxy)benzylamino]-propanamides and their salts with pharmaceutically acceptable acids with a high degree of purity, i.e. with a content of dibenzyl derivatives impurities lower than 0.03% by weight. The process is carried out by submitting a Schiff base intermediate to a reduction reaction with a reducing agent in an amount of organic solvent to allow the formation (and presence during a substantial portion of the reduction reaction) of a suspension of the Schiff base.
Core Innovation
The disclosure relates to producing high-purity 2-[4-(3- or 2-fluorobenzyloxy)benzylamino]propanamide compounds selected from safinamide and ralfinamide, including the respective R-enantiomers, the respective racemic mixtures, and pharmaceutically acceptable acid salts. The process targets a specific impurity and requires that the impurity content is lower than 0.03% by weight.
A Schiff base intermediate 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. The intermediate formation is carried out in a solvent selected from (C1–C5) lower alkanols at a temperature between 20°C and 30°C, and the solvent amount is selected to allow formation of a suspension of the Schiff base in a saturated solution of the Schiff base in the same solvent.
After completion of the iminoalkylation reaction, the Schiff base intermediate is submitted to a reduction reaction with sodium borohydride or potassium borohydride in an organic solvent selected from one or more (C1–C5) lower alkanols, optionally with water. The ratio of the organic solvent to the Schiff base is defined to maintain a suspension of the Schiff base into the saturated solution during a substantial portion of the reduction reaction course, and the aldehyde starting material used for preparing the Schiff base intermediate has a content of 3-(3- or 2-fluorobenzyl)-4-(3- or 2-fluorobenzyloxy)benzaldehyde impurity lower than 0.03% by weight.
Claims Coverage
The independent claims collectively cover 7 inventive features. The coverage links impurity control to a two-stage process for safinamide and ralfinamide products, includes isolated Schiff base embodiments, and specifies impurity limits for final R-enantiomer and racemic products and their pharmaceutically acceptable acid salts.
Solvent- and temperature-controlled iminoalkylation without molecular sieves
Obtaining the Schiff base intermediate from 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 (C1–C5) lower alkanols at a temperature between 20°C and 30°C to form a suspension of the Schiff base in a saturated solution in the same solvent.
Suspension maintained during reduction of the Schiff base intermediate
Submitting the Schiff base intermediate, after completion of the iminoalkylation reaction, to a reduction reaction with sodium borohydride or potassium borohydride in an organic solvent selected from one or more (C1–C5) lower alkanols, optionally with water, wherein the ratio of the organic solvent to the Schiff base allows formation and presence during a substantial portion of the reduction reaction course of a suspension of the Schiff base into the saturated solution in the same organic solvent.
Low-impurity aldehyde starting material
Using a 4-(3- or 2-fluorobenzyloxy)benzaldehyde starting material having a content of 3-(3- or 2-fluorobenzyl)-4-(3- or 2-fluorobenzyloxy)benzaldehyde impurity lower than 0.03% by weight for preparing the Schiff base intermediate.
Impurity-limited production of safinamide/ralfinamide products
Producing safinamide, ralfinamide, the respective R-enantiomer, or the respective racemic mixture, or their pharmaceutically acceptable acid salts, wherein the corresponding impurity is lower than 0.03% by weight.
Isolated R-enantiomer Schiff base compound
Providing the isolated Schiff base compound selected from (R)-2-[4-(3-fluorobenzyloxy)benzylideneamino]propanamide or (R)-2-[4-(2-fluorobenzyloxy)benzylideneamino]propanamide.
Safinamide R-enantiomer with impurity below 0.03% by weight
Safinamide R-enantiomer, or a salt thereof with a pharmaceutically acceptable acid, wherein the content of the corresponding impurity or a salt thereof is lower than 0.03% by weight.
Ralfinamide R-enantiomer with impurity below 0.03% by weight
Ralfinamide R-enantiomer, or a salt thereof with a pharmaceutically acceptable acid, wherein the content of the corresponding impurity or a salt thereof is lower than 0.03% by weight.
The claims combine a defined Schiff base iminoalkylation, borohydride reduction under suspension and saturated-solution conditions, and low-impurity aldehyde starting material to obtain safinamide and ralfinamide products, including enantiomers, racemic mixtures, isolated Schiff base compounds, and pharmaceutically acceptable acid salts, with impurity content below 0.03% by weight.
Stated Advantages
Produces safinamide and ralfinamide, including enantiomers, racemic mixtures, and pharmaceutically acceptable acid salts, with the content of the respective impurity lower than 0.03% by weight.
Avoids addition of molecular sieves during iminoalkylation.
Documented Applications
Not explicitly described in patent.
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