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Last Updated: March 29, 2024

Claims for Patent: 8,278,485


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Summary for Patent: 8,278,485
Title:Process for the production of 2-[4-(3- and 2-fluorobenzyloxy) benzylamino] propanamides
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.
Inventor(s): Barbanti; Elena (Cologno Monzese, IT), Caccia; Carla (Gallarate, IT), Salvati; Patricia (Arese, IT), Velardi; Francesco (Cameri, IT), Ruffilli; Tiziano (Vigliano Biellese, IT), Bogogna; Luigi (Vaprio d'Agogna, IT)
Assignee: Newron Pharmaceuticals S.p.A. (Bresso, IT)
Application Number:13/288,891
Patent Litigation and PTAB cases: See patent lawsuits and PTAB cases for patent 8,278,485
Patent Claims: 1. High purity (S)-2-[4-(3-fluorobenzyloxy)benzylamino]propanamide (safinamide) or (S)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (ralfinamide) of formula (Ia) or (Ib) ##STR00010## and pharmaceutically acceptable acid salts thereof, produced by the process of: submitting a Schiff base intermediate respectively of formula (VIa) or (VIb) ##STR00011## 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.

2. The product as in claim 1 wherein the catalytic hydrogenation is carried out by using an heterogeneous catalyst selected from nickel, rhodium, platinum and palladium catalysts on an inert support in the presence of a solvent selected from lower aliphatic (C.sub.1-C.sub.5) alkanols.

3. The product as in claim 1 wherein the catalyst is a palladium or platinum catalyst.

4. The product as in claim 1 wherein the catalyst is wet 5% Pt/C (50% H.sub.2O) or wet 10% Pd/C (50% H.sub.2O).

5. The product as in claim 1 wherein the pharmaceutically acceptable acid is methanesulfonic acid.

6. The product as in claim 1 wherein the hydrogen pressure is between 1 and 10 bars and the temperature is between 10.degree. C. and 70.degree. C.

7. The product as in claim 6 wherein the hydrogen pressure is between 3 and 6 bars and the temperature is between 25.degree. C. and 40.degree. C.

8. The product as in claim 1 wherein the catalytic hydrogenation is carried out on a Schiff base intermediate (VIa) or (VIb) which has been prepared through iminoalkylation of 4-(3-fluorobenzyloxy)benzaldehyde (IVa) or 4-(2-fluorobenzyloxy)benzaldehyde (IVb) ##STR00012## with L-alaninamide in the presence of a protic organic solvent.

9. The product as in claim 8 wherein the L-alaninamide is employed as an acid addition salt thereof in the presence of a base in an amount sufficient to set free L-alaninamide from its salt.

10. The product as in claim 8 where the catalytic hydrogenation of the Schiff base intermediate is performed on the same reaction mixture resulting from the completion of the iminoalkylation reaction under conditions which provoke the precipitation of said Schiff base intermediate to obtain a suspension of said intermediate in the same reaction solvent.

11. The product as in claim 8 wherein the Schiff base intermediate resulting from the completion of the iminoalkylation reaction is isolated before undergoing the catalytic hydrogenation step.

12. The product as in claim 8 wherein the 4-(3-fluorobenzyloxy)benzaldehyde or 4-(2-fluorobenzyloxy)benzaldehyde of formula (IVa) or (IVb) employed as the starting material to obtain the Schiff base intermediate of formula (VIa) or (VIb) contains less than 0.03% (by weight), of the respective impurities 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde (Va) or 3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzaldehyde (Vb) ##STR00013##

13. The product according to claim 12 wherein the 4-(3-fluorobenzyloxy)benzaldehyde (IVa) or 4-(2-fluorobezyloxy)benzaldehyde (IVb) is obtained by alkylation of 4-hydroxybenzaldehyde with, respectively, a 3-fluorobenzyl or 2-fluorobenzyl derivative (IIIa) or (IIIb) ##STR00014## where Y is a leaving group selected from Cl, Br, I, OSO.sub.2CH.sub.3 and OSO.sub.2--C.sub.6H.sub.4-pCH.sub.3, in the presence of a base, and is submitted to crystallization before the use in the successive reaction step.

14. The product as in claim 13 wherein Y is Cl.

15. The product as in claim 13 or 14 wherein the crystallization is carried out by adding an inert organic non-solvent to a solution of the 4-(3-fluorobenzyloxy)benzaldehyde (IVa) or 4-(2-fluorobenzyloxy)benzaldehyde (IVb) in an inert organic solvent.

16. The product as in claim 15 wherein the inert organic non-solvent is selected from lower aliphatic hydrocarbons and the inert organic solvent is selected from aromatic hydrocarbons.

17. The product as in claim 16 wherein the lower aliphatic hydrocarbon is n-hexane and the aromatic hydrocarbon is toluene.

18. The product as in any of claims 13 and 14 wherein the crystallization is carried out by dissolving the 4-(3-fluorobenzyloxy)benzaldehyde (IVa) or 4-(2-fluorobenzyloxy)benzaldehyde (IVb) in a hot solvent selected from cyclohexane, and a di(C3-C4)alkyl ether at reflux, and then cooling the solution to a temperature at or below room temperature.

19. The product as in any of claims 13 and 14 wherein the alkylation reaction is carried out under phase transfer conditions.

20. The product as in claim 19 wherein the alkylation under phase transfer condition is performed in a solid/liquid system wherein the reagents and the phase transfer catalyst are dissolved in a liquid organic phase and the solid phase is constituted by an inorganic base or a salt of 4-hydroxy benzaldehyde with said inorganic base.

21. The product as in claim 19 wherein the alkylation under phase transfer conditions is performed in a liquid/liquid system wherein the alkylating reagent 3-fluorobenzyl or 2-fluorobenzyl derivative of formula (IIIa) or (IIIb) is dissolved in a liquid organic phase and the 4-hydroxybenzaldehyde is dissolved in an aqueous phase as a salt with an inorganic base.

22. The product as in claim 19 wherein the phase transfer catalyst is selected from quaternary ammonium or phosphonium salts or polyethyleneglycols of low molecular weight.

23. The product of claim 22 wherein the amount of phase transfer catalyst employed is between 0.02 to 1 mole per mole of 4-hydroxybenzaldheyde.

24. The product as in claim 23 wherein the amount of phase-transfer catalyst is 0.1 to 1 mole per mole of 4-hydroxybenzaldehyde.

25. The product as in claim 20 wherein the organic solvent of the liquid organic phase is selected from dialkyl ethers and aromatic hydrocarbons.

26. The product as in claim 21 wherein the molar ratio between the alkylating reagent of formula (IIIa) or (IIIb), and 4-hydroxybenzaldehyde is between 0.6 and 1.5.

27. The product as in claim 20 wherein the temperature is between 60.degree. C. and 160.degree. C.

28. The product as in claim 20 wherein the inorganic base is selected from Na.sub.2CO.sub.3, K.sub.2CO.sub.3, NaOH and KOH, the temperature is between 80.degree. C. and 120.degree. C., and the ratio between the alkylating reagent of formula (IIIa) or (IIIb), and 4-hydroxybenzaldehyde is between 0.9 and 1.1.

29. The product as in claim 12 wherein safinamide or ralfinamide or their pharmaceutically acceptable acid salts, have a content of the respective impurity (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]prop- anamide (IIa) or (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide (IIIb) ##STR00015## or their pharmaceutically acceptable acid salts, which is lower than 0.03% (by weight).

30. The product as in claim 29 wherein the pharmaceutically acceptable acid is methanesulfonic acid and the content of the respective impurity of formula (IIa) or (IIb) as the salt with methanesulfonic acid is lower than 0.01% (by weight).

31. The product as in claim 3 wherein the catalyst is platinum.

32. The product as in claim 4 wherein the catalyst is wet 5% Pt/C (50% H.sub.2O).

33. The product as in claim 12 wherein the 4-(3-fluorobenzyloxy)benzaldehyde or 4-(2-fluorobenzyloxy)benzaldehyde of formula (IVa) or (IVb) employed as the starting material to obtain the Schiff base intermediate of formula (VIa) or (VIb) contains less than 0.01% (by weight), of the respective impurities 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde (Va) or 3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzaldehyde (Vb).

34. The product as in claim 18 wherein the hot solvent is diisopropylether.

35. The product as in claim 18 wherein the temperature is about 10-15.degree. C.

36. A method for treating epilepsy 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-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]prop- anamide of formula (IIa) ##STR00016## or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).

37. A method for treating Parkinson's disease 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-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide of formula (IIa) ##STR00017## or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).

38. A method for treating Alzheimer's disease 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-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide of formula (IIa) ##STR00018## or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).

39. A method for treating depression 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-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide of formula (IIa) ##STR00019## or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).

40. A method for treating restless legs syndrome 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-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide of formula (IIa) ##STR00020## or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).

41. A method for treating 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-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]prop- anamide of formula (IIa) ##STR00021## or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).

42. A method for treating pain conditions 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 (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide of formula (IIb) ##STR00022## or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).

43. A method for treating migraine 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 (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide of formula (IIb) ##STR00023## or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).

44. A method for treating bipolar 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 (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide of formula (IIb) ##STR00024## or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).

45. A method for treating depressions 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 (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide of formula (IIb) ##STR00025## or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).

46. A method for treating cardiovascular 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 (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide of formula (IIb) ##STR00026## or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).

47. A method for treating inflammatory 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 (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide of formula (IIb) ##STR00027## or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).

48. A method for treating urogenital 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 (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide of formula (IIb) ##STR00028## or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).

49. A method for treating metabolic 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 (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide of formula (IIb) ##STR00029## or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).

50. A method for treating 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 (S)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)-benzylamino]propanamide of formula (IIb) ##STR00030## or a pharmaceutically acceptable acid salt thereof is lower than 0.03% (by weight).

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