4-[[4-(trifluoromethoxy)phenyl]methoxy]piperidine

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 19.21 kg of tert-butyl 4-(4-trifluoromethoxybenzyloxy)piperidin-1-carboxylate and 50 L of ethanol were mixed, and stirred at 60° C. The mixture was mixed with 8.28 L of a concentrated hydrochloric acid, stirred at 60° C. for 2 hours, and concentrated under reduced pressure. 80 L of toluene was added to the residue; the mixture was extracted with 150 L of water; and further the water layer was washed with 40 L of toluene. 15.5 L of a 25% NaOH aqueous solution was added to the water layer; the mixture was extracted twice with 80 L and 40 L of toluene; the organic layers were combined and the organic layer was twice washed with 80 L of water; the organic layer was concentrated under reduced pressure; then, 20 L of ethanol was added to the residue; and the mixture was concentrated under reduced pressure to obtain 10.40 kg of a yellow oily target substance. stirred at 60° C. for 2 hours concentrated under reduced pressure 80 L of toluene was added to the residue the mixture was extracted with 150 L of water and further the water layer was washed with 40 L of toluene 15.5 L of a 25% NaOH aqueous solution was added to the water layer the mixture was extracted twice with 80 L and 40 L of toluene the organic layer was twice washed with 80 L of water the organic layer was concentrated under reduced pressure then, 20 L of ethanol was added to the residue and the mixture was concentrated under reduced pressure to obtain 10.40 kg of a yellow oily target substance

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-(4-(trifluoromethoxy)benzyloxy)piperidine (2.2 g, 8.00 mmol) in isopropanol (25 mL, 3 mL/mmol) was added DIPEA (3.6 mL, 0.02 mol) and 2,4-dichloro-1,3,5-triazine (1.2 g, 8.00 mmol) and the reaction was heated at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-chloro-4-(4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-1,3,5-triazine (800 mg, 57%) as a solid. Observed mass (M+1): 389.0. The reaction mixture was concentrated under reduced pressure extracted with EtOAc (2×40 mL) The organic extracts were washed with brine dried over sodium sulfate concentrated under reduced pressure Purification by silica gel column chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-(4-(trifluoromethoxy)benzyloxy)piperidine (2.2 g, 8.00 mmol) in isopropanol (25 mL, 3 mL/mmol) was added DIPEA (3.6 mL, 0.02 mol) and 2,4-dichloro-1,3,5-triazine (1.2 g, 8.00 mmol) and the reaction was heated at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-chloro-4-(4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-1,3,5-triazine (800 mg, 57%) as a solid. Observed mass (M+1): 389.0. The reaction mixture was concentrated under reduced pressure extracted with EtOAc (2×40 mL) The organic extracts were washed with brine dried over sodium sulfate concentrated under reduced pressure Purification by silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 4-(4-(trifluoromethoxy)benzyloxy)piperidine-1-carboxylate (1.7 g, 4.53 mmol) in CH2Cl2 (15 mL, 3 mL/mmol) was added TFA (10 mL) and the mixture was stirred for 2 h at RT. The reaction mixture was concentrated under reduced pressure, taken up in chloroform, filtered and washed with diethyl ether to provide 4-(4-(trifluoromethoxy)benzyloxy) piperidine (1.2 g, 96%) as TFA salt. Observed mass (M+1): 276 The reaction mixture was concentrated under reduced pressure filtered washed with diethyl ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 4-(4-(trifluoromethoxy)benzyloxy)piperidine-1-carboxylate was dissolved in CH2Cl2 (40 mL) and TFA (4 mL) was added. The light yellow solution was stirred at RT for 20 h, after which time complete Boc deprotection was evident by LC-MS. The solution was concentrated under reduced pressure providing product as a TFA salt in 65-95% overall yield. The material was purified to obtain a salt or free based using catch and release with strong cation exchange chromatography (SCX-2) washing first with MeOH, then with 2M NH3 in MeOH. The solution was concentrated under reduced pressure

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 19.21 kg of tert-butyl 4-(4-trifluoromethoxybenzyloxy)piperidin-1-carboxylate and 50 L of ethanol were mixed, and stirred at 60° C. The mixture was mixed with 8.28 L of a concentrated hydrochloric acid, stirred at 60° C. for 2 hours, and concentrated under reduced pressure. 80 L of toluene was added to the residue; the mixture was extracted with 150 L of water; and further the water layer was washed with 40 L of toluene. 15.5 L of a 25% NaOH aqueous solution was added to the water layer; the mixture was extracted twice with 80 L and 40 L of toluene; the organic layers were combined and the organic layer was twice washed with 80 L of water; the organic layer was concentrated under reduced pressure; then, 20 L of ethanol was added to the residue; and the mixture was concentrated under reduced pressure to obtain 10.40 kg of a yellow oily target substance. stirred at 60° C. for 2 hours concentrated under reduced pressure 80 L of toluene was added to the residue the mixture was extracted with 150 L of water and further the water layer was washed with 40 L of toluene 15.5 L of a 25% NaOH aqueous solution was added to the water layer the mixture was extracted twice with 80 L and 40 L of toluene the organic layer was twice washed with 80 L of water the organic layer was concentrated under reduced pressure then, 20 L of ethanol was added to the residue and the mixture was concentrated under reduced pressure to obtain 10.40 kg of a yellow oily target substance

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 19.21 kg of tert-butyl 4-(4-trifluoromethoxybenzyloxy)piperidin-1-carboxylate and 50 L of ethanol were mixed, and stirred at 60° C. The mixture was mixed with 8.28 L of a concentrated hydrochloric acid, stirred at 60° C. for 2 hours, and concentrated under reduced pressure. 80 L of toluene was added to the residue; the mixture was extracted with 150 L of water; and further the water layer was washed with 40 L of toluene. 15.5 L of a 25% NaOH aqueous solution was added to the water layer; the mixture was extracted twice with 80 L and 40 L of toluene; the organic layers were combined and the organic layer was twice washed with 80 L of water; the organic layer was concentrated under reduced pressure; then, 20 L of ethanol was added to the residue; and the mixture was concentrated under reduced pressure to obtain 10.40 kg of a yellow oily target substance. stirred at 60° C. for 2 hours concentrated under reduced pressure 80 L of toluene was added to the residue the mixture was extracted with 150 L of water and further the water layer was washed with 40 L of toluene 15.5 L of a 25% NaOH aqueous solution was added to the water layer the mixture was extracted twice with 80 L and 40 L of toluene the organic layer was twice washed with 80 L of water the organic layer was concentrated under reduced pressure then, 20 L of ethanol was added to the residue and the mixture was concentrated under reduced pressure to obtain 10.40 kg of a yellow oily target substance

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-(4-(trifluoromethoxy)benzyloxy)piperidine (2.2 g, 8.00 mmol) in isopropanol (25 mL, 3 mL/mmol) was added DIPEA (3.6 mL, 0.02 mol) and 2,4-dichloro-1,3,5-triazine (1.2 g, 8.00 mmol) and the reaction was heated at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-chloro-4-(4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-1,3,5-triazine (800 mg, 57%) as a solid. Observed mass (M+1): 389.0. The reaction mixture was concentrated under reduced pressure extracted with EtOAc (2×40 mL) The organic extracts were washed with brine dried over sodium sulfate concentrated under reduced pressure Purification by silica gel column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 4-(4-(trifluoromethoxy)benzyloxy)piperidine-1-carboxylate (1.7 g, 4.53 mmol) in CH2Cl2 (15 mL, 3 mL/mmol) was added TFA (10 mL) and the mixture was stirred for 2 h at RT. The reaction mixture was concentrated under reduced pressure, taken up in chloroform, filtered and washed with diethyl ether to provide 4-(4-(trifluoromethoxy)benzyloxy) piperidine (1.2 g, 96%) as TFA salt. Observed mass (M+1): 276 The reaction mixture was concentrated under reduced pressure filtered washed with diethyl ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 4-(4-(trifluoromethoxy)benzyloxy)piperidine-1-carboxylate was dissolved in CH2Cl2 (40 mL) and TFA (4 mL) was added. The light yellow solution was stirred at RT for 20 h, after which time complete Boc deprotection was evident by LC-MS. The solution was concentrated under reduced pressure providing product as a TFA salt in 65-95% overall yield. The material was purified to obtain a salt or free based using catch and release with strong cation exchange chromatography (SCX-2) washing first with MeOH, then with 2M NH3 in MeOH. The solution was concentrated under reduced pressure