(3R)-1-[(4-fluorophenyl)methyl]-3-methylpiperazine

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

Procedure: To a solution of (2R)-2-methyl-piperazine (4.5 g, 45 mmol) in ethanol (80 mL) was added 4-fluorobenzyl chloride (5.38 mL, 45.0 mmol) and sodium hydrogen carbonate (11.3 g, 135 mmol). The reaction was refluxed overnight, cooled and concentrated. The remaining residue was diluted with dichloromethane and washed with water. The organic layer was separated and concentrated to give a clear oil. Chromatography on silica gel gave the title compound (5.0 g). The reaction was refluxed overnight cooled concentrated The remaining residue was diluted with dichloromethane washed with water The organic layer was separated concentrated to give a clear oil

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

Procedure: To a solution of (2R)-2-methyl-piperazine (4.5 g, 45 mmol) in ethanol (80 mL) was added 4-fluorobenzyl chloride (5.38 mL, 45.0 mmol) and sodium hydrogen carbonate (11.3 g, 135 mmol). The reaction was refluxed overnight, cooled and concentrated. The remaining residue was diluted with dichloromethane and washed with water. The organic layer was separated and concentrated to give a clear oil. Chromatography on silica gel gave the title compound (5.0 g). The reaction was refluxed overnight cooled concentrated The remaining residue was diluted with dichloromethane washed with water The organic layer was separated concentrated to give a clear oil

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 7-chloro-benzo[1,4]dioxin-2-one (0.845 g, 4.81 mmol) in toluene (25 mL) was added (3R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (1.003 g, 4.81 mmol). The resulting mixture was heated to 95° C. overnight. The reaction was cooled to ambient temperature, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (˜1 g). The reaction was cooled to ambient temperature filtered concentrated in vacuo

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

Procedure: To a solution of glycolic acid (0.70 g, 9.2 mmol), 4-dimethylaminopyridine (catalytic) and pyridine (1.52 mL, 18.6 mmol) in dry dichloromethane (20 mL) was added trimethylsilylchloride (2.39 mL, 2.05 mmol) dropwise. The reaction was stirred at ambient temperature for 4 hours. The reaction was then cooled to 0° C. and catalytic dimethylformamide (3 drops) was added followed by addition of oxalyl chloride. The reaction was stirred at 0° C. for one hour and then 30 minutes at ambient temperature. The reaction was cooled back to 0° C. and (3R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (2.11 g, 10.12 mmol) was added as a solution in pyridine (2.45 mL, 30.4 mmol). The reaction was allowed to warm to ambient temperature and stirred for 2 hours. The reaction was neutralized with 1N hydrochloric acid and extracted with dichloromethane (2×). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (1.84 g). The reaction was then cooled to 0° C. The reaction was stirred at 0° C. for one hour 30 minutes at ambient temperature The reaction was cooled back to 0° C. to warm to ambient temperature stirred for 2 hours extracted with dichloromethane (2×) dried over magnesium sulfate filtered concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (3R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (3 g, 14.4 mmol) in dichloromethane (40 mL) was added triethylamine (2.0 mL, 14.4 mmol). The reaction was cooled to 0° C. and chloroacetyl chloride was added (1.1 mL, 14.4 mmol). The reaction was allowed to warm to ambient temperature and stirred for 2 hours. The reaction is diluted with dichloromethane and washed with 10% citric acid. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (3.9 g). to warm to ambient temperature washed with 10% citric acid The organic layer was separated dried over magnesium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of (2R)-2-methyl-piperizine (4.5 g, 45 mmol) in ethanol (80 mL) was added 4-fluorobenzyl chloride (5.38 mL, 45.0 mmol) and sodium hydrogen carbonate (11.3 g, 135 mmol). The reaction was refluxed overnight, cooled and concentrated. The remaining residue was diluted with dichloromethane and washed with water. The organic layer was separated and concentrated to give a clear oil. Chromatography on silica gel gave the title compound (5.0 g). The reaction was refluxed overnight cooled concentrated The remaining residue was diluted with dichloromethane washed with water The organic layer was separated concentrated to give a clear oil

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 7-chloro-benzo[1,4]dioxin-2-one (0.845 g, 4.81 mmol) in toluene (25 mL) was added (3R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (1.003 g, 4.81 mmol). The resulting mixture was heated to 95° C. overnight. The reaction was cooled to ambient temperature, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (˜1 g). The reaction was cooled to ambient temperature filtered concentrated in vacuo

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

Procedure: To a solution of glycolic acid (0.70 g, 9.2 mmol), 4-dimethylaminopyridine (catalytic) and pyridine (1.52 mL, 18.6 mmol) in dry dichloromethane (20 mL) was added trimethylsilylchloride (2.39 mL, 2.05 mmol) dropwise. The reaction was stirred at ambient temperature for 4 hours. The reaction was then cooled to 0° C. and catalytic dimethylformamide (3 drops) was added followed by addition of oxalyl chloride. The reaction was stirred at 0° C. for one hour and then 30 minutes at ambient temperature. The reaction was cooled back to 0° C. and (3R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (2.11 g, 10.12 mmol) was added as a solution in pyridine (2.45 mL, 30.4 mmol). The reaction was allowed to warm to ambient temperature and stirred for 2 hours. The reaction was neutralized with 1N hydrochloric acid and extracted with dichloromethane (2×). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (1.84 g). The reaction was then cooled to 0° C. The reaction was stirred at 0° C. for one hour 30 minutes at ambient temperature The reaction was cooled back to 0° C. to warm to ambient temperature stirred for 2 hours extracted with dichloromethane (2×) dried over magnesium sulfate filtered concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (3R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (3 g, 14.4 mmol) in dichloromethane (40 mL) was added triethylamine (2.0 mL, 14.4 mmol). The reaction was cooled to 0° C. and chloroacetyl chloride was added (1.1 mL, 14.4 mmol). The reaction was allowed to warm to ambient temperature and stirred for 2 hours. The reaction is diluted with dichloromethane and washed with 10% citric acid. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (3.9 g). to warm to ambient temperature washed with 10% citric acid The organic layer was separated dried over magnesium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of (2R)-2-methyl-piperizine (4.5 g, 45 mmol) in ethanol (80 mL) was added 4-fluorobenzyl chloride (5.38 mL, 45.0 mmol) and sodium hydrogen carbonate (11.3 g, 135 mmol). The reaction was refluxed overnight, cooled and concentrated. The remaining residue was diluted with dichloromethane and washed with water. The organic layer was separated and concentrated to give a clear oil. Chromatography on silica gel gave the title compound (5.0 g). The reaction was refluxed overnight cooled concentrated The remaining residue was diluted with dichloromethane washed with water The organic layer was separated concentrated to give a clear oil

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

Procedure: To a solution of (2R)-2-methyl-piperazine (4.5 g, 45 mmol) in ethanol (80 mL) was added 4-fluorobenzyl chloride (5.38 mL, 45.0 mmol) and sodium hydrogen carbonate (11.3 g, 135 mmol). The reaction was refluxed overnight, cooled and concentrated. The remaining residue was diluted with dichloromethane and washed with water. The organic layer was separated and concentrated to give a clear oil. Chromatography on silica gel gave the title compound (5.0 g). The reaction was refluxed overnight cooled concentrated The remaining residue was diluted with dichloromethane washed with water The organic layer was separated concentrated to give a clear oil

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 7-chloro-benzo[1,4]dioxin-2-one (0.845 g, 4.81 mmol) in toluene (25 mL) was added (3R)-1-(4-fluoro-benzyl)-3-methyl-piperazine (1.003 g, 4.81 mmol). The resulting mixture was heated to 95° C. overnight. The reaction was cooled to ambient temperature, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (˜1 g). The reaction was cooled to ambient temperature filtered concentrated in vacuo