Methanol → Safinamide

HRID 2061151Notes

Reaction equation

HRID 2061151 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:19]=[CH:18][C:10]([CH:11]=[N:12][C@@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])=[CH:9][CH:8]=1.CO.C(OCC)(=O)C>[Pt].O>[CH3:17][C@H:13]([NH:12][CH2:11][C:10]1[CH:18]=[CH:19][C:7]([O:6][CH2:5][C:4]2[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)[C:14]([NH2:16])=[O:15]

Participants

6

Reactant 3

HCID 887MethanolHCID 8857Ethyl AcetateHCID 23659732(S)-(+)-2-[4-(Fluorobenzyloxy-Benzylamino)propionamide]

Product 1

HCID 131682SafinamideYield 94.9%

Reagents, catalysts & solvents 2

HCID 23939PlatinumCatalystHCID 962WaterSolvent

Procedure

An autoclave is loaded with (S)-2-[4-(3-fluorobenzyloxy)benzylidene-amino]propanamide (16.0 g; 0.053 mol), prepared as described above, and wet (50% H2O) Pt/C 5% (1.7 kg: Engelhard S.r.l., Rome, Italy) and methanol (90 mL) is added thereto. The autoclave is purged from air with nitrogen and then hydrogen is introduced at 5.0 bars. The reaction is kept at 5.0 bar and at 35° C. for 1 hour. After cooling to room temperature and elimination of the catalyst by filtration, the solvent is distilled off under reduced pressure until a residue of approximately 30 g is obtained. To this residue a mixture of ethyl acetate (150 mL) and H2O (110 mL) is added and the heterogeneous mixture is heated to 40° C., until two clear phases are obtained. These two phases are separated and the aqueous layer is extracted with 50 mL of ethyl acetate at 40° C. The organic phases are collected and evaporated to dryness. The procedure is repeated twice by adding every time 90 mL of ethyl acetate to make the product anhydrous. 95 mL of n-heptane are then added slowly and under stirring to the residue. The mixture is then maintained under stirring for 3 hours at 20° C. The solid formed is collected by filtration, washed with n-hetpane (15 mL) and dried under reduced pressure to give 15.2 g (94.8% yield) of safinamide with a HPLC purity of 99.8 (area %, see Example 17A) and a content of (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propanamide lower than 0.005% by weight measured by HPLC (see Example 17B).

Workup

  1. customprepared
  2. customThe autoclave is purged from air with nitrogen
  3. additionhydrogen is introduced at 5.0 bars
  4. filtrationelimination of the catalyst by filtration
  5. distillationthe solvent is distilled off under reduced pressure until a residue of approximately 30 g
  6. customis obtained
  7. additionis added
  8. temperaturethe heterogeneous mixture is heated to 40° C., until two clear phases
  9. customare obtained
  10. customThese two phases are separated
  11. extractionthe aqueous layer is extracted with 50 mL of ethyl acetate at 40° C
  12. customThe organic phases are collected
  13. customevaporated to dryness
  14. additionby adding every time 90 mL of ethyl acetate
  15. addition95 mL of n-heptane are then added slowly
  16. temperatureThe mixture is then maintained
  17. stirringunder stirring for 3 hours at 20° C
  18. customThe solid formed
  19. filtrationis collected by filtration
  20. washwashed with n-hetpane (15 mL)
  21. customdried under reduced pressure

Sources & evidence

ORD record
ord-f7cee2a5d21a45978f571dd59587bb78
Source dataset
uspto-grants-2012_10
Patent number
US08278485B2

Reaction notes

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