324750-04-1

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

Procedure: To a solution of (S)-1-benzyl-3-ethylpiperazine (650 mg, 3.22 mmol) in DME (10 mL) at room temperature, was added NaH (60% suspension in mineral oil, 144 mg, 3.50 mmol) and the mixture was stirred for 45 min. Methyl 2-chlorobenzoxazole-4-carboxylate (510 mg, 2.42 mmol) was added to the reaction mixture and the reaction was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in hexanes) to afford (S)-methyl 2-(4-benzyl-2-ethylpiperazine-1-yl)benzoxazole-4-carboxylate (0.87 g, 71%) as an oily solid. 1H NMR and MS consistent. the reaction was stirred at room temperature for 17 h The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added solvent removed under reduced pressure The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in hexanes)

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

Procedure: To a solution of (S)-1-benzyl-3-ethylpiperazine (650 mg, 3.22 mmol) in DME (10 mL) at room temperature, was added NaH (60% suspension in mineral oil, 144 mg, 3.50 mmol) and the mixture was stirred for 45 min. Methyl 2-chlorobenzoxazole-4-carboxylate (510 mg, 2.42 mmol) was added to the reaction mixture and the reaction was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in hexanes) to afford (S)-methyl 2-(4-benzyl-2-ethylpiperazine-1-yl)benzoxazole-4-carboxylate (0.87 g, 71%) as an oily solid. 1H NMR and MS consistent. the reaction was stirred at room temperature for 17 h The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added solvent removed under reduced pressure The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in hexanes)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: LiAlH4 (1 M solution in THF, 11 mL, 11.0 mmol) was added drop wise to solution of (S)-1-benzyl-3-ethylpiperazine-2-one (0.8 g, 3.66 mmol) in THF (30 mL) at 0° C. The reaction mixture was stirred at 65° C. for 17 h, then cooled 0° C. and quenched sequentially with H2O (0.7 mL), 10% NaOH (1 mL) and H2O (1.5 mL). Diethylether (100 mL) was added to the reaction mixture, and stirring was continued for 1.5 h. The solid was filtered off, the filtrate was concentrated and dried in vacuum to afford (S)-1-benzyl-3-ethylpiperazine (0.67 g, 87%) as an oily solid. 1H NMR and MS consistent. cooled 0° C. quenched sequentially with H2O (0.7 mL), 10% NaOH (1 mL) and H2O (1.5 mL) Diethylether (100 mL) was added to the reaction mixture stirring was continued for 1.5 h The solid was filtered off the filtrate was concentrated dried in vacuum

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: LiAlH4 (1 M solution in THF, 11 mL, 11.0 mmol) was added drop wise to solution of (S)-1-benzyl-3-ethylpiperazine-2-one (0.8 g, 3.66 mmol) in THF (30 mL) at 0° C. The reaction mixture was stirred at 65° C. for 17 h, then cooled 0° C. and quenched sequentially with H2O (0.7 mL), 10% NaOH (1 mL) and H2O (1.5 mL). Diethylether (100 mL) was added to the reaction mixture, and stirring was continued for 1.5 h. The solid was filtered off, the filtrate was concentrated and dried in vacuum to afford (S)-1-benzyl-3-ethylpiperazine (0.67 g, 87%) as an oily solid. 1H NMR and MS consistent. cooled 0° C. quenched sequentially with H2O (0.7 mL), 10% NaOH (1 mL) and H2O (1.5 mL) Diethylether (100 mL) was added to the reaction mixture stirring was continued for 1.5 h The solid was filtered off the filtrate was concentrated dried in vacuum

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

Procedure: A solution of 8.1 gm (34.9 mmol) 2(S)-ethyl-4-benzyl-3,6-dioxopiperazine in 50 mL tetrahydrofuran was added dropwise via addition funnel to a solution of 75 mL (75 mMol) lithium aluminum hydride (1M in tetrahydrofuran) and the mixture was heated at reflux for 2.5 h. The reaction was then cooled in an ice bath and was treated sequentially with 3 mL deionized water, 3 mL 5N sodium hydroxide, and 9 mL deionized water. The resulting slurry was allowed to stir for 1 hour and was then filtered. The recovered salts were rinsed with 100 mL tetrahydrofuran and 100 mL dichloromethane. The filtrate was concentrated in vacuo to afford 7.03 g (99%) of the desired piperazine. the mixture was heated at reflux for 2.5 h The reaction was then cooled in an ice bath was treated sequentially with 3 mL was then filtered The recovered salts were rinsed with 100 mL tetrahydrofuran and 100 mL dichloromethane The filtrate was concentrated in vacuo

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

Procedure: A solution of 8.1 gm (34.9 mmol) 2(S)-ethyl-4-benzyl-3,6-dioxopiperazine in 50 mL tetrahydrofuran was added dropwise via addition funnel to a solution of 75 mL (75 mMol) lithium aluminum hydride (1M in tetrahydrofuran) and the mixture was heated at reflux for 2.5 h. The reaction was then cooled in an ice bath and was treated sequentially with 3 mL deionized water, 3 mL 5N sodium hydroxide, and 9 mL deionized water. The resulting slurry was allowed to stir for 1 hour and was then filtered. The recovered salts were rinsed with 100 mL tetrahydrofuran and 100 mL dichloromethane. The filtrate was concentrated in vacuo to afford 7.03 g (99%) of the desired piperazine. the mixture was heated at reflux for 2.5 h The reaction was then cooled in an ice bath was treated sequentially with 3 mL was then filtered The recovered salts were rinsed with 100 mL tetrahydrofuran and 100 mL dichloromethane The filtrate was concentrated in vacuo

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

Procedure: To a solution of (S)-1-benzyl-3-ethylpiperazine (650 mg, 3.22 mmol) in DME (10 mL) at room temperature, was added NaH (60% suspension in mineral oil, 144 mg, 3.50 mmol) and the mixture was stirred for 45 min. Methyl 2-chlorobenzoxazole-4-carboxylate (510 mg, 2.42 mmol) was added to the reaction mixture and the reaction was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in hexanes) to afford (S)-methyl 2-(4-benzyl-2-ethylpiperazine-1-yl)benzoxazole-4-carboxylate (0.87 g, 71%) as an oily solid. 1H NMR and MS consistent. the reaction was stirred at room temperature for 17 h The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added solvent removed under reduced pressure The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in hexanes)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: LiAlH4 (1 M solution in THF, 11 mL, 11.0 mmol) was added drop wise to solution of (S)-1-benzyl-3-ethylpiperazine-2-one (0.8 g, 3.66 mmol) in THF (30 mL) at 0° C. The reaction mixture was stirred at 65° C. for 17 h, then cooled 0° C. and quenched sequentially with H2O (0.7 mL), 10% NaOH (1 mL) and H2O (1.5 mL). Diethylether (100 mL) was added to the reaction mixture, and stirring was continued for 1.5 h. The solid was filtered off, the filtrate was concentrated and dried in vacuum to afford (S)-1-benzyl-3-ethylpiperazine (0.67 g, 87%) as an oily solid. 1H NMR and MS consistent. cooled 0° C. quenched sequentially with H2O (0.7 mL), 10% NaOH (1 mL) and H2O (1.5 mL) Diethylether (100 mL) was added to the reaction mixture stirring was continued for 1.5 h The solid was filtered off the filtrate was concentrated dried in vacuum

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

Procedure: To a solution of the product from example 69 part b) (4.74 g) in DCM (150 ml) was added (BOC)2O (5.52 g) and the reaction stirred at RT for 48 h. The reaction was concentrated under reduced pressure. The crude product was purified by chromatography (silica, (0-10% EtOAc/isohexane as eluent)), to give the sub-titled compound as a colourless oil (6.09 g). The reaction was concentrated under reduced pressure The crude product was purified by chromatography (silica, (0-10% EtOAc/isohexane as eluent))

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

Procedure: To a solution of the product of example 69 part a) (5.68 g) in THF (30 ml) at 0° C. was added LAH (100 ml, 1.0M in THF) dropwise. The resulting solution was heated at reflux overnight. The reaction mixture was cooled to RT and quenched by cautious sequential addition of water (3.8 ml), 15% aq NaOH (3.8 ml), and water (11.4 ml). The precipitous solution was diluted with EtOAc and filtered through Celite. The residue was washed with EtOAc (3×100 ml) and the combined organics concentrated in vacuo. The crude product was dissolved in DCM, filtered through Celite and the solvent removed in vacuo to give the sub-titled product as a yellow oil (4.74 g). The resulting solution was heated at reflux overnight quenched by cautious sequential addition of water (3.8 ml), 15% aq NaOH (3.8 ml), and water (11.4 ml) The precipitous solution was diluted with EtOAc filtered through Celite The residue was washed with EtOAc (3×100 ml) the combined organics concentrated in vacuo The crude product was dissolved in DCM filtered through Celite the solvent removed in vacuo

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

Procedure: To a solution of the product from example 69 part b) (4.74 g) in DCM (150 ml) was added (BOC)2O (5.52 g) and the reaction stirred at RT for 48 h. The reaction was concentrated under reduced pressure. The crude product was purified by chromatography (silica, (0-10% EtOAc/isohexane as eluent)), to give the sub-titled compound as a colourless oil (6.09 g). The reaction was concentrated under reduced pressure The crude product was purified by chromatography (silica, (0-10% EtOAc/isohexane as eluent))

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

Procedure: To a solution of the product of example 69 part a) (5.68 g) in THF (30 ml) at 0° C. was added LAH (100 ml, 1.0M in THF) dropwise. The resulting solution was heated at reflux overnight. The reaction mixture was cooled to RT and quenched by cautious sequential addition of water (3.8 ml), 15% aq NaOH (3.8 ml), and water (11.4 ml). The precipitous solution was diluted with EtOAc and filtered through Celite. The residue was washed with EtOAc (3×100 ml) and the combined organics concentrated in vacuo. The crude product was dissolved in DCM, filtered through Celite and the solvent removed in vacuo to give the sub-titled product as a yellow oil (4.74 g). The resulting solution was heated at reflux overnight quenched by cautious sequential addition of water (3.8 ml), 15% aq NaOH (3.8 ml), and water (11.4 ml) The precipitous solution was diluted with EtOAc filtered through Celite The residue was washed with EtOAc (3×100 ml) the combined organics concentrated in vacuo The crude product was dissolved in DCM filtered through Celite the solvent removed in vacuo