Sodium Hydroxide → HCID 131729858, compound

Participants

Reaction Conditions

Reaction Steps

To a clean, dry, nitrogen-purged 250 ml flask were charged racemic cis-(1-benzyl-4-methyl-piperidine-3-yl)-methylamine bis hydrochloride (20.0 g, 68.7 mmol), di-p-toluoyl-L-tartaric acid (L-DPTT) (15.9 g, 41.2 mmol) and methanol (100 ml). A solution of sodium hydroxide (5.5 g, 137.3 mmol in water (100 ml)) was added to the reaction at a rate to maintain the temperature below 30° C. The reaction was heated to between 70-80° C. and held at this temperature for at least 60 minutes. The reaction was cooled to 5-15° C. over at least 4 hours and held at this temperature for at least 12 hours. The solids were filtered and washed with a 1:1 mixture of MeOH:water (60 ml). The wet-cake was returned to the 250 ml flask and methanol (100 ml) and water (100 ml) were charged. The reaction was heated to between 70-80° C. and held at this temperature for at least 120 minutes. The reaction was cooled to 5-15° C. over at least 4 hours and held at this temperature for at least 12 hours. The solids were filtered and washed with a 1:1 mixture of MeOH:water (60 ml). The wet-cake was sampled for purity (99.4% ee) to ensure an additional repulp was not necessary. After drying under vacuum at 40-50° C. for at least 24 hours with a slight nitrogen bleed, the title compound (11.9 g, 28.9 mmol) was isolated in 42.1% yield (98.6% enantiomeric excess, 0.63% trans isomer by GC (Cyclosil B column 30 m×I.D. 0.25 mm; Inlet Temp 250; 2.0 ml/min flow rate; 15 min run; 160 C isothermal method.

Provenance & Evidence