Acetic Acid → tert-Butyl 4-hydroxy-[1,4'-bipiperidine]-1'-carboxylate

Participants

Reaction Steps

1-tert-Butoxycarbonyl-4-piperidone (55 g, 0.276 mol, 1.15 eq) and 4-hydroxypiperidine (24.3 g, 0.24 mol, 1 eq) were stirred at room temperature in ethanol (160 ml) and acetic acid (16 ml) for 25 minutes. To the solution was added 2.4 g of 5% palladium on carbon type 87L Johnson Matthey catalyst. The reaction was then hydrogenated under a pressure of 3.5 bar at room temperature for 72 hours. The catalyst was filtered off and the mixture partitioned between water (320 ml) and iso-propyl acetate (360 ml). The aqueous was collected, and washed twice further with iso-propyl acetate (2×360 ml). The aqueous was then basified (10M aqueous sodium hydroxide, 25 ml) and the aqueous washed twice with MTBE (2×194 ml). Solvent (194 ml) was removed by distillation under vacuum (−0.7 bar, 65° C. oil bath). THF (777 ml) was added and the solution again concentrated by removal of solvent (777 ml, −0.7 bar, 65° C. oil bath). THF (485 ml) was added to the solution and solvent (485 ml) removed by vacuum distillation (−0.7 bar, 70° C.). Half of the solution was evaporated at this point to give 4-(hydroxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester as an off-white solid (25.31 g, 74% yield; 99.6% purity HPLC area %).

Provenance & Evidence