2-methyl-1-piperazin-1-ylpropan-2-ol

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

Procedure: [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-2-methyl-propyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 2-methyl-1-piperazin-1-yl-propan-2-ol (example 18a) in an analogous manner as described in example 25. LR-MS: 651.4 [(M+H)+]

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

Procedure: [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-2-methyl-propyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 2-methyl-1-piperazin-1-yl-propan-2-ol (example 18a) in an analogous manner as described in example 25. LR-MS: 651.4 [(M+H)+]

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: piperazine (6.88 g, 80.0 mmol) was dissolved in ethanol (40 mL), and 1-chloro-2-methyl-2-propanol (2.18 g, 20.0 mmol) was added thereto, and then, the mixture was stirred at 110° C. for 6 hours. After the mixture was left to cool to room temperature, the solvent was evaporated. Then, ethyl acetate was added to the residue, and the precipitated solid was removed by filtration. The solvent of the filtrate was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=90/10) to give 2-methyl-1-(piperazin-1-yl)propan-2-ol (1.89 g, 11.96 mmol, 60%). After the mixture was left to cool to room temperature the solvent was evaporated Then, ethyl acetate was added to the residue the precipitated solid was removed by filtration The solvent of the filtrate was removed under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/methanol=90/10)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: piperazine (6.88 g, 80.0 mmol) was dissolved in ethanol (40 mL), and 1-chloro-2-methyl-2-propanol (2.18 g, 20.0 mmol) was added thereto, and then, the mixture was stirred at 110° C. for 6 hours. After the mixture was left to cool to room temperature, the solvent was evaporated. Then, ethyl acetate was added to the residue, and the precipitated solid was removed by filtration. The solvent of the filtrate was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=90/10) to give 2-methyl-1-(piperazin-1-yl)propan-2-ol (1.89 g, 11.96 mmol, 60%). After the mixture was left to cool to room temperature the solvent was evaporated Then, ethyl acetate was added to the residue the precipitated solid was removed by filtration The solvent of the filtrate was removed under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/methanol=90/10)

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

Procedure: A solution of 563 (460 mg, 1.78 mmol) and TFA (5 ml) in DCM (20 ml) was stirred at rt for 5 h. The reaction mixture was concentrated (azeotropes with DCM), diluted with water, stirred for 10 min. The pH was adjusted to around 10 with 1N NaOH, and the alkaline solution was extracted with DCM. The organic extract was dried over anhydrous magnesium sulfate, filtered, concentrated under high vacuum to afford the desired product 564 (170 mg, 1.07 mmol, 60% yield) as a dark orange sticky solid. The crude product was used in the next step without any further purification. MS (m/z): 159.13 (M+H). The reaction mixture was concentrated (azeotropes with DCM) diluted with water the alkaline solution was extracted with DCM The organic extract was dried over anhydrous magnesium sulfate filtered concentrated under high vacuum

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into 7 mL of DMSO, 500 mg (2.12 mmol) of Compound E was dissolved, and then 0.95 mL (6.36 mmol) of DBU and 1.50 g (9.50 mmol) of 1-(2-hydroxy-2-methylpropyl)piperazine were added thereto, followed by stirring at 140° C. for about 2 hours. After completion of the reaction, the reaction mixture was extracted by adding chloroform and water, and the organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by silica gel column chromatography (3% methanol-chloroform) and then recrystallized from a mixed solvent of hexane-ethyl acetate to obtain 250 mg of Compound 1 as a white solid (yield: 33%). After completion of the reaction the reaction mixture was extracted by adding chloroform and water the organic layer was washed with water and brine dried over anhydrous magnesium sulfate After evaporation of the solvent the resulting residue was purified by silica gel column chromatography (3% methanol-chloroform) recrystallized from a mixed solvent of hexane-ethyl acetate