Safinamide Impurity 9 synthesis

Yield:1000370-28-4 83%

Reaction Conditions:

Stage #1: 3-(2-fluoro-benzyl)-4-(2-fluoro-benzyloxy)-benzaldehyde;(S)-alaninamide hydrochloridewith triethylamine in methanol at 20; for 1 h;
Stage #2: with hydrogen;platinum on carbon in methanol;water at 35; under 3750.38 Torr; for 3 - 5 h;

Steps:

8.b

To 3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzaldehyde (3.56 g, 0.0105 mol) in a 50 mL flask, a solution previously prepared by cautiously adding under stirring triethylamine (1.2 g, 0.01 19 mol) to a 17 mL methanol solution of L-alaninamide hydrochloride (1.48 g, 0.01 19 mol), is added at room temperature. This reaction mixture is stirred for 1 hour at room temperature (precipitation of the corresponding imine occurs) , and then it is transferred to a 0.18 L autoclave and 0.34 g of wet (50% H₂O) Pt/C 5% are added to the mixture.The air is purged from the autoclave with nitrogen and then hydrogen is introduced at 5.0 bar.The reaction is performed at a temperature of 35 °C for 3-5 hours. After cooling to room temperature and eliminating the catalyst by filtration, the solvent is distilled off under reduced pressure until a residue of approximately 6.5 g is obtained. To this residue water (22 mL) is added and kept at this temperature under stirring for at least two hours.The obtained crystals are filtered and washed with water. The title compound is obtained in 83% yield (0.00872 mol); m.p. 161°C (capillary).¹H-NMR: (CDCl₃, 300 MHz, 298K) δ (ppm, with respect to TMS): 1.32 (3H, d, J= 6.7 Hz, CH₃); 1.97 (IH, bs, NH); 3.22 (IH, q, J= 6.7 Hz, CH-CO); 3.67 (2H, ABq, J= 12.8 Hz, diastereotopic H Of NCH₂); 4.03 (2H, s, CH₂); 5.12 (2H, s, OCH₂); 5.98 (IH, bs, NH₂); 6.89 (IH, d, 8.3 Hz, aromatic H ortho to CH₂NH and aromatic CH); 6.95-7.40 (1OH, m, aromatic H).¹³C-NMR: (CDCl₃, 75.4 MHz, 298K) δ (ppm): 19.6 (CH₃); 29.2 (CH₂); 52.0 (NHCH₂); 57.7 (H₂NCOCH); 63.8 (OCH₂); 1 1 1.7 (aromatic CH); 1 15.2 (d, Jc F= 21.9 Hz, aromatic CH), 1 15.3 (d, Jc F= 21.3 Hz, aromatic CH); 124.0 (d, Jc F= 3.5 Hz, aromatic CH); 124.3 (d, Jc F= 2.9 Hz, aromatic CH); 124.3 (d, Jc F= 14.4 Hz, quaternary aromatic C); 127.5 (aromatic CH); 127.6 (d, Jc F= 15.0 Hz, quaternary aromatic C); 127.8 (d, Jc F= 7.5 Hz, aromatic CH); 128.8 (quaternary aromatic C); 129.0- 130.0 (m, 2 aromatic CH); 130.5 (aromatic CH); 131.3 (d, Jc F= 4.6 Hz, aromatic CH); 131.8 (quaternary aromatic C); 155.6 (quaternary aromatic C); 160.4 (d, Jc F= 245.8 Hz, quaternary aromatic C); 161.2 (d, Jc F= 244.6 Hz, quaternary aromatic C); 178.2 (CONH₂).

References:

WO2009/74478,2009,A1 Location in patent:Page/Page column 51-52