1-benzyl-N-propan-2-ylpiperidin-4-amine

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

Procedure: A solution of 4-chlorobutyryl chloride (5.3 mL, 47.4 mmol) in dichloromethane (400 mL) was added dropwise to a mixture of 1-benzyl-4-(isopropylamino)piperidine (10 g, 43.07 mmol) and DIPEA (9.0 mL, 51.7 mmol) in dichloromethane (200 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The solution was then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1) to give 5.0 g of the title intermediate as viscous oil (35% yield). at room temperature for 2 h The solution was then washed with saturated sodium bicarbonate, brine dried over magnesium sulfate concentrated in vacuo The residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1)

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

Procedure: To a mixture of 1-benzyl-4-(isopropylamino)piperidine (8 g, 34.45 mmol) and DIPEA (7.2 mL, 41.3 mmol) in 200 mL of dichloromethane was added dropwise a solution of 2-chloroacetyl chloride (3.01 mL, 37.9 mmol) in dichloromethane (400 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The reaction mixture was then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1) to give 5.35 g of the title intermediate as a viscous oil (50% yield). at room temperature for 2 h The reaction mixture was then washed with saturated sodium bicarbonate, brine dried over magnesium sulfate concentrated in vacuo The resulting residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1)

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

Procedure: To a mixture of 1-benzyl-4-(isopropylamino)piperidine (8 g, 34.45 mmol) and DIPEA (7.2 mL, 41.3 mmol) in 200 mL of dichloromethane was added dropwise a solution of 2-chloroacetyl chloride (3.01 mL, 37.9 mmol) in dichloromethane (400 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The reaction mixture was then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1) to give 5.35 g of the title intermediate as a viscous oil (50% yield). at room temperature for 2 h The reaction mixture was then washed with saturated sodium bicarbonate, brine dried over magnesium sulfate concentrated in vacuo The resulting residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1)

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

Procedure: To a 50 L 3-neck round-bottom reaction flask equipped with a mechanical stirrer, temperature probe, nitrogen inlet and cooling bath was added 4-amino-1-benzylpiperidine (2,000 g, 10.5 mol) and dichloromethane (20 L). Acetone (610.5 g, 10.5 mol) was added and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then cooled to 0° C. to 5° C. with an ice/methanol bath and sodium triacetoxyborohydride (2,673 g, 12.6 mol) was added while maintaining the temperature of the reaction mixture below 25° C. The cooling bath was then removed and the reaction mixture was stirred until less than 1% starting material was present by gas chromatograhy (GC) analysis (about 3 hours). Concentrated hydrochloric acid was added until the pH of the reaction mixture was 7 (about 500 mL). The resulting slurry was filtered through a polypropylene filter pad and the solids were washed with dichloromethane (2×2 L). The solids were saved for use after concentration of the filtrate. The filtrate was concentrated at 40° C. until no condensate remained. In a 40 L separatory funnel, the solids and distillation residue were dissolved in water (15 L) and concentrated hydrochloric acid was added until the pH of the solution was 3 (about 2.5 L). The aqueous layer was then washed with dichloromethane (2×2 L). The pH of the aqueous layer was adjusted to 11 to 12 with 50% aqueous sodium hydroxide solution (about 4.5 L) and this mixture was extracted with dichloromethane (5×3 L). The organic layers were combined, decolorized with charcoal (50 g) and dried over anhydrous magnesium sulfate (200 g). The solids were filtered off using a glass fiber filter pad and the filtrate was concentrated until no condensate remained to afford the title compound (2,336 g, 96% yield). To a 50 L 3-neck round-bottom reaction flask equipped with a mechanical stirrer temperature probe, nitrogen inlet and cooling bath The reaction mixture was then cooled to 0° C. to 5° C. with an ice/methanol bath while maintaining the temperature of the reaction mixture below 25° C The cooling bath was then removed the reaction mixture was stirred until less than 1% was present by gas chromatograhy (GC) analysis (about 3 hours) Concentrated hydrochloric acid was added until the pH of the reaction mixture The resulting slurry was filtered through a polypropylene filter pad the solids were washed with dichloromethane (2×2 L) The filtrate was concentrated at 40° C. until no condensate In a 40 L separatory funnel, the solids and distillation residue were dissolved in water (15 L) concentrated hydrochloric acid was added until the pH of the solution The aqueous layer was then washed with dichloromethane (2×2 L) this mixture was extracted with dichloromethane (5×3 L) dried over anhydrous magnesium sulfate (200 g) The solids were filtered off filter pad the filtrate was concentrated until no condensate

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

Procedure: A solution of 4-chlorobutyryl chloride (5.3 mL, 47.4 mmol) in dichloromethane (400 mL) was added dropwise to a mixture of 1-benzyl-4-(isopropylamino)piperidine (10 g, 43.07 mmol) and DIPEA (9.0 mL, 51.7 mmol) in dichloromethane (200 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The solution was then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1) to give 5.0 g of the title intermediate as viscous oil (35% yield). at room temperature for 2 h The solution was then washed with saturated sodium bicarbonate, brine dried over magnesium sulfate concentrated in vacuo The residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1)

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-amino-1-benzylpiperidine (45.8 g, 0.24 mol) and acetone (531 mL) was stirred at room temperature for 12 hours. The reaction mixture was then reduced to ca. 150 mL in vacuo. To this mixture was added methanol (100 mL) and the resulting mixture was cooled to 5° C. in an ice/water bath. Sodium triacetoxyborohydride (61.2 g, 0.29 mol) in methanol (350 mL), previously cooled to 5° C. in an ice/water bath, was added and this reaction mixture was stirred at 5° C. for 0.5 hours. The ice/water bath was removed and the reaction mixture was stirred for 2 hours at room temperature and then re-cooled to 5° C. in ice/water bath. To this mixture was added concentrated hydrochloric acid (75 mL) until the pH of the reaction mixture was about 3. This mixture was stirred for 1 hour and then concentrated in vacuo to about 600 mL and 1 N aqueous hydrochloric acid (200 mL) was added to dissolve the solids. The aqueous layer was washed with isopropyl acetate (400 mL) and the layers were separated. The aqueous layer was adjusted to pH 12 with 10 N aqueous sodium hydroxide (200 mL) and isopropylacetate (600 mL) was added. This mixture was stirred for 1 hour at room temperature and then the layers were separated and the organic layer washed with saturated aqueous sodium chloride solution (600 mL) and dried over sodium sulfate (80 g). The sodium sulfate was filtered off and washed with ethyl acetate (20 mL). The solvent was removed in vacuo to give 52.0 g of the title intermediate as a yellow oil (95% yield). was added The ice/water bath was removed the reaction mixture was stirred for 2 hours at room temperature re-cooled to 5° C. in ice/water bath To this mixture was added concentrated hydrochloric acid (75 mL) until the pH of the reaction mixture This mixture was stirred for 1 hour concentrated in vacuo to about 600 mL and 1 N aqueous hydrochloric acid (200 mL) was added to dissolve the solids The aqueous layer was washed with isopropyl acetate (400 mL) the layers were separated was added This mixture was stirred for 1 hour at room temperature the layers were separated the organic layer washed with saturated aqueous sodium chloride solution (600 mL) dried over sodium sulfate (80 g) The sodium sulfate was filtered off washed with ethyl acetate (20 mL) The solvent was removed in vacuo

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

Procedure: A solution of 4-chlorobutyryl chloride (5.3 m]L, 47.4 mmol) in dichloromethane (400 mL) was added dropwise to a mixture of 1-benzyl-4-(isopropylamino)piperidine (10 g, 43.07 mmol) and DIPEA (9.0 mL, 51.7 mmol) in dichloromethane (200 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The solution was then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1) to give 5.0 g of the title intermediate as viscous oil (35% yield). at room temperature for 2 h The solution was then washed with saturated sodium bicarbonate, brine dried over magnesium sulfate concentrated in vacuo The residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1)

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

Procedure: To a mixture of 1-benzyl-4-(isopropylamino)piperidine (8 g, 34.45 mmol) and DIPEA (7.2 mL, 41.3 mmol) in 200 mL of dichloromethane was added dropwise a solution of 2-chloroacetyl chloride (3.01 mL, 37.9 mmol) in dichloromethane (400 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The reaction mixture was then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1) to give 5.35 g of the title intermediate as a viscous oil (50% yield). at room temperature for 2 h The reaction mixture was then washed with saturated sodium bicarbonate, brine dried over magnesium sulfate concentrated in vacuo The resulting residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1)

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

Procedure: To a mixture of 1-benzyl-4-(isopropylamino)piperidine (8 g, 34.45 mmol) and DIPEA (7.2 mL, 41.3 mmol) in 200 mL of dichloromethane was added dropwise a solution of 2-chloroacetyl chloride (3.01 mL, 37.9 mmol) in dichloromethane (400 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The reaction mixture was then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1) to give 5.35 g of the title intermediate as a viscous oil (50% yield). at room temperature for 2 h The reaction mixture was then washed with saturated sodium bicarbonate, brine dried over magnesium sulfate concentrated in vacuo The resulting residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1)

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-amino-1-benzylpiperidine (45.8 g, 0.24 mol) and acetone (531 mL) was stirred at room temperature for 12 hours. The reaction mixture was then reduced to ca. 150 mL in vacuo. To this mixture was added methanol (100 mL) and the resulting mixture was cooled to 5° C. in an ice/water bath. Sodium triacetoxyborohydride (61.2 g, 0.29 mol) in methanol (350 mL), previously cooled to 5° C. in an ice/water bath, was added and this reaction mixture was stirred at 5° C. for 0.5 hours. The ice/water bath was removed and the reaction mixture was stirred for 2 hours at room temperature and then re-cooled to 5° C. in ice/water bath. To this mixture was added concentrated hydrochloric acid (75 mL) until the pH of the reaction mixture was about 3. This mixture was stirred for 1 hour and then concentrated in vacuo to about 600 mL and 1 N aqueous hydrochloric acid (200 mL) was added to dissolve the solids. The aqueous layer was washed with isopropyl acetate (400 mL) and the layers were separated. The aqueous layer was adjusted to pH 12 with 10 N aqueous sodium hydroxide (200 mL) and isopropylacetate (600 mL) was added. This mixture was stirred for 1 hour at room temperature and then the layers were separated and the organic layer washed with saturated aqueous sodium chloride solution (600 mL) and dried over sodium sulfate (80 g). The sodium sulfate was filtered off and washed with ethyl acetate (20 mL). The solvent was removed in vacuo to give 52.0 g of the title intermediate as a yellow oil (95% yield). was added The ice/water bath was removed the reaction mixture was stirred for 2 hours at room temperature re-cooled to 5° C. in ice/water bath To this mixture was added concentrated hydrochloric acid (75 mL) until the pH of the reaction mixture This mixture was stirred for 1 hour concentrated in vacuo to about 600 mL and 1 N aqueous hydrochloric acid (200 mL) was added to dissolve the solids The aqueous layer was washed with isopropyl acetate (400 mL) the layers were separated was added This mixture was stirred for 1 hour at room temperature the layers were separated the organic layer washed with saturated aqueous sodium chloride solution (600 mL) dried over sodium sulfate (80 g) The sodium sulfate was filtered off washed with ethyl acetate (20 mL) The solvent was removed in vacuo

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

Procedure: A solution of 4-chlorobutyryl chloride (5.3 mL, 47.4 mmol) in dichloromethane (400 mL) was added dropwise to a mixture of 1-benzyl-4-(isopropylamino)piperidine (10 g, 43.07 mmol) and DIPEA (9.0 mL, 51.7 mmol) in dichloromethane (200 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The solution was then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1) to give 5.0 g of the title intermediate as viscous oil (35% yield). at room temperature for 2 h The solution was then washed with saturated sodium bicarbonate, brine dried over magnesium sulfate concentrated in vacuo The residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1)

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

Procedure: To a mixture of 1-benzyl-4-(isopropylamino)piperidine (8 g, 34.45 mmol) and DIPEA (7.2 mL, 41.3 mmol) in 200 mL of dichloromethane was added dropwise a solution of 2-chloroacetyl chloride (3.01 mL, 37.9 mmol) in dichloromethane (400 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The reaction mixture was then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1) to give 5.35 g of the title intermediate as a viscous oil (50% yield). at room temperature for 2 h The reaction mixture was then washed with saturated sodium bicarbonate, brine dried over magnesium sulfate concentrated in vacuo The resulting residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1)