Process for the preparation of safinamide mesylate intermediate
The present application provides methods for the synthesis of intermediates in the synthesis of Safinamide or a pharmaceutically acceptable salt thereof herein Safinamide Mesylate, that is substantially free of impurities.
1. A method for the preparation of a compound, comprising:
a condensation reaction of 4-hydroxybenzaldehyde of formula II with 1-(chloromethyl)-3-fluorobenzene of formula III, using potassium carbonate, and potassium iodide in a solvent, and removing the solvent after completion of the condensation reaction, therewith producing crude 4-((3-fluorobenzyl)oxy)benzaldehyde of formula IV;
treating the crude with n-heptane to remove genotoxic impurities;
dissolving the treated crude in dichloromethane and treating the solution with potassium carbonate; and
treating the treated solution with n-heptane to afford 4-((3-fluorobenzyl)oxy)benzaldehyde of formula V having a purity greater than 99%.
2. The method of claim 1 , wherein the solvent comprises an alcohol selected from the group consisting of methanol, ethanol, isopropanol, and butanol.
3. The method of claim 1 , wherein the solvent comprises a nitrile selected from the group consisting of acetonitrile and propionitrile.
4. The method of claim 1 , wherein the solvent comprises a cyclic ether selected from the group consisting of tetrahydrofuran, furan, and ethylene oxide.
5. The method of claim 1 , wherein the solvent comprises at least one of DMSO (dimethyl Sulfoxide), DMF (dimethylformamide), and DMA (dimethylacetamide).
6. The method of claim 1 , wherein the resulting 4-((3-fluorobenzyl)oxy)benzaldehyde of formula V has a purity of greater than 99.9%.
7. The method of claim 1 , comprising using the pure 4-((3-fluorobenzyl)oxy)benzaldehyde of formula V for the synthesis of safinamide mesylate of formula I.
8. The method of claim 7 , wherein the resulting safinamide mesylate of formula I is crystalline.
9. The method of claim 7 , wherein the resulting safinamide mesylate of formula I has a purity of greater than 99% and is prepared by reacting pure 4-((3-fluorobenzyl)oxy)benzaldehyde of formula V with L-alaninamide hydrochloride in the presence of methanol and sodium cyanoborohydride to get safinamide and further reacting the safinamide with methane sulfonic acid using ethyl acetate as solvent to obtain safinamide mesylate.
10. The method of claim 9 , wherein the resulting safinamide mesylate of formula I has a purity of greater than 99.9%.
11. The method of claim 1 , wherein the resulting crude formula IV, before the first treatment with n-heptane, has a purity of greater than 99%.
12. The method of claim 1 , wherein the resulting crude formula IV, before the first treatment with n-heptane, has a purity of greater than 99.9%.
13. The method of claim 1 , wherein removing the solvent comprises evaporating the solvent under vacuum.