1-benzyl-3-(trifluoromethyl)piperazine

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1-benzyl-3-(trifluoromethyl)piperazine 34a (1.0 mmol) and pyridine (1.1 mmol) in DCM (5 mL), is added ethyl chloroformate (1.1 mmol). The resulting mixture is stirred at rt for 1 h. After the reaction is complete, the reaction mixture is diluted with DCM (15 mL) and washed with water. The organic layer is separated, dried over Na2SO4, filtered, and concentrated to afford ethyl 4-benzyl-2-(trifluoromethyl)piperazine-1-carboxylate 34b, which is used without purification. MS (m/z) (M+1)+: 317.1. washed with water The organic layer is separated dried over Na2SO4 filtered concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Benzyl-3-(trifluoromethyl)piperazine 34a (4.1 mmol) is dissolved in MeOH (50 mL) followed by addition of AcOH (2.0 mL) and 5% mol of Pd/C. The flask is charged with a hydrogen balloon and stirred for 12 h. The mixture is filtered over celite and the filtrate is concentrated to afford 2-(trifluoromethyl)piperazine 35a, which is used without further purification. MS (m/z) (M+1)+: 155.1. The mixture is filtered over celite the filtrate is concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-Benzyl-3-(trifluoromethyl)piperazine (0.74 g, 3.0 mmol; Intermediate 44) was dissolved in acetic acid (70 mL) and water (5 mL). Pd, 5% on carbon, (0.074 g) was added and =hydrogenation was performed at 3 bar and 70° C. overnight. The reaction mixture was filtered through Celite and the pad was rinsed with water (5 mL). Solvents were removed in vacuo, toluene (20 mL) added to the residue, followed by re-concentration in vacuo to remove residual water. The desired product sublimated on the evaporator and 0.15 g (32%) was collected as a white powder. 1H NMR (270 MHz, methanol-d4) δ ppm 2.67-2.87 (m, 3H) 2.91-3.05 (m, 2H) 3.12-3.21 (m, 1H). MS (ESI+) m/z 155. *Previously described in Rec. Trav. Chim. Pays-Bas 1995, 114, 97-102. was performed at 3 bar and 70° C. overnight The reaction mixture was filtered through Celite the pad was rinsed with water (5 mL) Solvents were removed in vacuo, toluene (20 mL) added to the residue followed by re-concentration in vacuo to remove residual water The desired product sublimated on the evaporator and 0.15 g (32%) was collected as a white powder

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 3,3,3-trifluoro-2-oxopropanal (0.31 g, 2.3 mmol; Intermediate 43) in DMF (10 mL) was cooled to 0° C. and a solution of N-benzylethane-1,2-diamine (0.37 g, 2.72 mmol) in DMF (10 mL) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was redissolved in THF (5 mL) and citrate buffer (5.3 mL; 0.4 M), followed by NaBH3CN (0.31 g, 4.9 mmol), were added. The resulting mixture was stirred at room temperature overnight. The mixture was made basic (pH 8) with aqueous NaOH (8 mL; 1 M) and the aqueous layer was extracted twice with DCM (15 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by LC-MS prep to give 1-benzyl-3-(trifluoromethyl)piperazine (66 mg, 12%). HPLC 94%, RT=1.25 min (System A; 10-97% MeCN over 3 min). 1H NMR (270 MHz, CDCl3) δ ppm 2.77 (s, 2H) 3.17-3.31 (m, 1H) 3.32-3.64 (m, 3H) 3.83-4.02 (m, 1H) 4.13-4.31 (m, 2H) 6.68 (s, 1H) 7.30-7.55 (m, 5H). MS (ESI+) m/z 245. *Previously described in Rec. Trav. Chim. Pays-Bas 1995, 114, 97-102. the mixture was concentrated in vacuo The residue was redissolved in THF (5 mL) were added The resulting mixture was stirred at room temperature overnight the aqueous layer was extracted twice with DCM (15 mL) The combined organic layers were dried (Na2SO4) concentrated The residue was purified by LC-MS prep