[Synthesis]
GENERAL STEPS: 9.72 kg of ethyl 4-hydroxypiperidine-1-carboxylate and 10.0 L of triethylamine were dissolved in 15.0 L of toluene and the resulting solution was cooled to below 10 °C. To this solution, 7.07 kg of methanesulfonyl chloride was slowly added dropwise at a temperature below 25 °C, followed by continued stirring for 1 hour at below 25 °C. Next, 5.00 kg of 4-trifluoromethoxyphenol, 10 L of toluene, 17.7 L of 25% aqueous sodium hydroxide and 6.24 kg of 50% aqueous tetra-n-butyl ammonium chloride were added to the reaction solution. The mixture was heated to reflux for 2 hours (internal temperature was maintained at 88°C). After completion of the reaction, the mixture was cooled and the aqueous layer was separated and discarded. The organic layer was washed with 10 L of water. Subsequently, 14.2 kg of potassium hydroxide and 10 L of ethanol were added to the washed organic layer and the mixture was heated to reflux for 4 hours (internal temperature maintained at 98 °C). After cooling, concentration was carried out under reduced pressure. To the concentrated residue, 50 L of toluene was added and the organic layer was washed sequentially with 25 L of water, 25 L of brine and 31 L of aqueous ammonium chloride. The washed toluene solution was concentrated under reduced pressure. The concentrated residue was dissolved in a solvent mixture of 5 L of isopropanol, 50 L of water and 2.5 L of 25% aqueous sodium hydroxide to form a homogeneous solution, which was subsequently cooled to below 10 °C. After the crystals precipitated, stirring was continued below 10 °C for 1 h. The precipitate was then collected by filtration. The crystals were washed with 15 L of water and dried in air to give 6.67 kg of 4-(4-trifluoromethoxyphenoxy)piperidine (isolated yield: 90.9%). 1H-NMR (300 MHz, CDCl3) δ ppm: 1.41 (2H, dddd), 1.90 (2H, m), 2.55 (2H, dddd), 2.92 (2H, dddd), 3.33 (1H, brs), 4.39 (1H, tt), 7.03 (2H, d), 7.25 (2H, d). |