p-Toluenesulfonic acid → Tert-butyl 4-((2-oxo-2-(3-(trifluoromethyl)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

Charge (2-Amino-1-(3-trifluoromethyl-phenyl)-ethanone)-, p-toluene sulfonate (1:1) (913 g, 2.43 mol) and 1-tert-Butoxycarbonylisonipecotic acid (623 g, 2.73 mol, 1.12 eq) along with THF (2.75 L) and EtOAc (5.5 L) and cool to 0-5° C. Add 1.2 equivalents of propylphosphonic anhydride (T3P) (1.2 eq, 2.91 mol, 1.512 L of a 50% solution in EtOAc) and maintain the reaction temperature at 0-5° C. during addition. Stir for 10 min, then add N-methylmorpholine (566 g, 5.6 mol, 2.3 eq) holding the temperature below 5° C. during addition. Warm the reaction to room temperature and after 10 hours, cool in an ice bath and add water (7.3 L). Separate the layers and wash the aqueous layer with EtOAc (2.75 L). Combine the organic layers and wash with 0.5M aqueous sodium bicarbonate solution (2.75 L). Wash the organic layer with saturated aqueous sodium chloride (2.75 L), then treat the resulting organic layer with sodium sulfate and filter. Remove the solvent via distillation down to ˜4.6 L. Add back heptane (11 L) while removing solvent via distillation until the final volume reaches ˜11 L. Cool to 50° C. and seed. Hold the resulting slurry at 50° C. for 3 h, then cool the slurry to room temperature and stir for 2 h. Filter the solids and wash the cake, first with 10% EtOAc in heptane (2 L) then with heptane (2 L). After drying in a vacuum oven at 60° C. for 3 h, 800 g (79%) of 4-[2-Oxo-2-(3-trifluoromethyl-phenyl)-ethylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester is obtained as a white solid.

Provenance & Evidence