1,1-Dimethylethyl 3-oxo-4-(phenylmethyl)-1-piperazinecarboxylate

Step 1 Sodium hydride (80 mg, 2.0 mmol, 60percent in mineral oil) was added to a solution of 4-tert-butyloxycarbonyl-piperazin-2-one (200 mg, 1.0 mmol) in dimethylformamide (5.0 mL) at 0° C. The reaction was stirred at 0° C. for 0.5 h. To this mixture was added benzyl bromide (300 uL, 2.5 mmol) and the reaction was stirred for 2 h at room temperature. The reaction mixture was quenched with a dilute aqueous solution of sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine and dried over anhydrous sodium sulfate. Purification of the crude residue by chromatography over silica gel using 30percent ethyl acetate in hexane gave 4-tert-butyloxycarbonyl-2-benzyl-piperazin-2-one (174 mg, 60percent yield). [0350] Hydrochloric acid (0.25 mL, 1.00 mmol, 4 M in 1, 4-dioxane) was added to a solution of 4-tert-butyloxycarbonyl-2-benzyl-piperazin-2-one (174 mg, 0.60 mmol) in 1, 4-dioxane (1.0 mL). The mixture was stirred overnight. The reaction was concentrated to give 2-benzyl-piperazin-2-one hydrochloride as an off-white solid (130 mg, 97percent yield). [0351] 4, 5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4, 5-dihydro-imidazole-1-carbonyl chloride (example 3) was reacted with 2-benzyl-piperazin-2-one hydrochloride using the procedure as described in example 5 to give 4-[4, 5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4, 5-dihydro-imidazole-carbonyl]-1-benzyl-piperazin-2-one. It was then dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to give 4-[4, 5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4, 5-dihydro-imidazole-carbonyl]-1-benzyl-piperazin-2-one hydrochloride as an off-white powder (65 mg, 89percent yield). LR-MS (APCI): 695.6 [(M+H)+].Step 2: To a solution of the product of Step 1 (1.17 g, 5.87 MMOL) in DMF (25 ml) at RT was added NaH (60percent dispersion in mineral oil, 352 mg, 8.8 mmol, 1.5 eq) and the resulting mixture was stirred at RT for 2 h. Benzyl bromide (0.84 ML, 7.04 mmol, 1.2 eq) was added and the reaction was heated at 70 °C for 16 h. The reaction mixture was cooled to RT and the excess NaH was quenched carefully by the dropwise addition of MeOH. The solvent was evaporated in vacuo and the residue was chromatographed (SI02, 70percent EtOAc/hexanes) to give the product (1.6 g, 95percent) as a white SOLID. H NMR (CDCI3, 300 MHz) 8 7.28 (5H, m), 4.62 (2H, s), 4.16 (2H, s), 3.58 (2H, m, J = 5. 1 Hz), 3.25 (2H, m, J = 5. 4 HZ), 1.46 (9H, s).Step 2: To a solution of the product of Step 1 (1.17 g, 5.87 mmol) in DMF (25 ml) at RT was added NaH (60percent dispersion in mineral oil, 352 mg, 8.8 mmol, 1.5 eq) and the resulting mixture was stirred at RT for 2 h. Benzyl bromide (0.84 ML, 7.04 mmol, 1.2 eq) was added and the reaction was heated at 70 °C for 16 h. The reaction mixture was cooled to RT and the excess NaH was quenched carefully by the dropwise addition of MeOH. The solvent was EVAPORATED IN VACUO and the residue was chromatographed on silica (70percent EtOAc/hexanes) to give the product (1.6 g, 95percent) as a white solid.'H NMR (CDC13, 300 MHz) 6 7.28 (5H, m), 4.62 (2H, s), 4.16 (2H, s), 3.58 (2H, m, J = 5.1 Hz), 3.25 (2H, m, J = 5.4 Hz), 1.46 (9H, s).To a solution of the product of Step 4 (10.0 g, 50.0 mmol) in anhydrous DMF(250 ml) in an ice-water bath were added sodium hydride (2.40 g, 60.0 mmol) andbenzyl chloride (6.60 g, 52.5 mmol). The mixture was stirred at RT for 4.5 h. Thereaction was quenched with water (10 ml), diluted with CHTo a solution of the product of Step 7 (10.0 g, 50.0 mmol) in anhydrous DMF(250 ml) in an ice-water bath were added sodium hydride (2.40 g, 60.0 mmol) andbenzyl chloride (6.60 g, 52.5 mmol). The mixture was stirred at RT for 4.5 h. Thereaction was quenched with water (10 ml), diluted with CHStep 1tert-butyl 4-benzyl-3-oxopiperazine-1-carboxylateDi-tert-butyl dicarbonate (750 mg, 3.44 mmol) was added to a solution of piperazine-2-one (344 mg, 3.44 mmol) in CH2C12 (13 mL). The solution was stirred at room temperature for 16 hours, then concentrated under vacuum. The residue was dissolved in N, Ndimethylformamide (10 mL) and stirred under nitrogen as sodium hydride (60percent dispersion in oil, 0.25 g, 6.25 mmol) was added at room temperature. The mixture was stirred for 30 minutes, then benzyl bromide (0.532 mL, 4.47 mmol) was added. The mixture was stirred under nitrogen for 1 hour, and the reaction was quenched by cautious addition of water (3 mL). Finally, the mixture was diluted with water (50 mL) and stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration and washed with water (40 mL), then dried under vacuum to the titled compound (0.82 g, 82percent). ‘H NMR (400 MHz, methanol-d4) ppm 1.46 (s, 9H), 3.30 - 3.33 (m, 2H), 3.60 (t, J = 5.2 Hz, 2H), 4.11 (s, 2H), 4.62 (s, 2H), 7.25 - 7.37 (m, 5H); MS (ESI) m/z 291 (M+H).Step 1 Step 1: 1-Benzyl-4-(tert-butyloxycarbonyl)piperazin-2-thione A mixture of Step 2 1-Benzyl-piperazin-2-one To a solution of 35 mL of TFA in dichloromethane was added 4-benzyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (10.39 g, 35.8 mmol) in portions. After 18 hours the solution was concentrated via rotary evaporator and H20 was added. The pH was adjusted to 12 with 4M NaOH. The mixture was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-benzyl-piperazin-2-one (6.29 g, 92%) as an oil.The product of part a) (420 mg) was stirred in TFA (10 ml) for 30 min, then 0 concentrated in vacuo to give the sub-title compound as an oil (415 mg). EPO A 60% dispersion of sodium hydride in mineral oil (3.6 g, 150 mmol, 1.5 equiv) was added in portions to a solution of tert- butyl 3-oxopiperazine-l-carboxylate (20.02 g, 100 mmol, 1 equiv) in anhydrous THF (400 mL) at 5 C and the mixture was stirred at room temperature for 1.5 hours. Benzyl bromide (14.27 mL, 120 mmol, 1.2 equiv) was added and the mixture was stirred at room temperature for 15 hours. Water (100 mL) was carefully added to quench the reaction and the mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with saturated brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with heptanes (200 mL) to give tert-butyl 4-benzyl-3-oxopiperazine-l- carboxylate (23.5 g, 81% yield) as a white solid.Step 1 4-Benzyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester Sodium hydride (60%, 18.11 g, 452 mmol) in mineral oil was triturated with 35 hexanes, dried under a stream of nitrogen and taken up in 1500 mL of THF. To the slurry at 0 C. was added 3-oxo-piperazine-1-carboxylic acid tert-butyl ester (75.057 g, 200.4 mmol) in portions over 15 min. After 90 minutes benzyl bromide (71.01 g, 415.1 mmol) was added and the mixture was warmed to room temperature for 18 hours. The solution was quenched with H2O and extracted with Et2O. The combined organic layers were washed with H2O, washed with brine, dried over MgSO4. Concentration in vacuo gave a crude solid which was recrystallized from hexane to afford 4-benzyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (83.5 g, 76%) as a white crystalline solid.Sodium hydride (80 mg, 2.0 mmol, 60% in mineral oil) was added to a solution of 4-tert-butyloxycarbonyl-piperazin-2-one (200 mg, 1.0 mmol) in dimethylformamide (5.0 mL) at 0 C. The reaction was stirred at 0 C. for 0.5 h. To this mixture was added benzyl bromide (300 uL, 2.5 mmol) and the reaction was stirred for 2 h at room temperature. The reaction mixture was quenched with a dilute aqueous solution of sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine and dried over anhydrous sodium sulfate. Purification of the crude residue by chromatography over silica gel using 30% ethyl acetate in hexane gave 4-tert-butyloxycarbonyl-2-benzyl-piperazin-2-one (174 mg, 60% yield). [0350] Hydrochloric acid (0.25 mL, 1.00 mmol, 4 M in 1, 4-dioxane) was added to a solution of 4-tert-butyloxycarbonyl-2-benzyl-piperazin-2-one (174 mg, 0.60 mmol) in 1, 4-dioxane (1.0 mL). The mixture was stirred overnight. The reaction was concentrated to give 2-benzyl-piperazin-2-one hydrochloride as an off-white solid (130 mg, 97% yield). [0351] 4, 5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4, 5-dihydro-imidazole-1-carbonyl chloride (example 3) was reacted with 2-benzyl-piperazin-2-one hydrochloride using the procedure as described in example 5 to give 4-[4, 5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4, 5-dihydro-imidazole-carbonyl]-1-benzyl-piperazin-2-one. It was then dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to give 4-[4, 5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4, 5-dihydro-imidazole-carbonyl]-1-benzyl-piperazin-2-one hydrochloride as an off-white powder (65 mg, 89% yield). LR-MS (APCI): 695.6 [(M+H)+].

Molecular Weight:290.36
XLogP3:1.9
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:290.16304257
Monoisotopic Mass:290.16304257
Topological Polar Surface Area:49.8
Heavy Atom Count:21
Complexity:384
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes