1-benzylpiperidin-4-amine;dihydrochloride

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

Procedure: In this reference example, 5.24 g of 1-benzyl-4-amino-piperidine dihydrochloride, 3.02 g of o-nitrobenzaldehyde, 2.02 g of triethylamine and 30 ml of methanol are mixed and stirred at room temperature for one hour. The resultant solution is cooled with ice and stirred. To the stirred solution, 1 g of sodium borohydride is added little by little over a period of one hour. Then, the mixture is brought back to room temperature and stirred at room temperature for 2 hours. The resultant solution is poured into 200 ml of ice water and extracted with ether. The organic layer is washed with water, dried and concentrated. The oily residue is dissolved in 20 ml of ethanol. The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate. The white crystals deposited are separated by filtration, washed with 20 ml of ethyl acetate and dried to obtain 5.70 g of a crude product. The crude product is recrystallized from hot ethanol to obtain 2.90 g of the desired product. stirred is brought back to room temperature stirred at room temperature for 2 hours extracted with ether The organic layer is washed with water dried concentrated The oily residue is dissolved in 20 ml of ethanol The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate The white crystals deposited are separated by filtration washed with 20 ml of ethyl acetate dried to obtain 5.70 g of a crude product The crude product is recrystallized from hot ethanol

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

Procedure: In this reference example, 5.24 g of 1-benzyl-4-amino-piperidine dihydrochloride, 3.02 g of o-nitrobenzaldehyde, 2.02 g of triethylamine and 30 ml of methanol are mixed and stirred at room temperature for one hour. The resultant solution is cooled with ice and stirred. To the stirred solution, 1 g of sodium borohydride is added little by little over a period of one hour. Then, the mixture is brought back to room temperature and stirred at room temperature for 2 hours. The resultant solution is poured into 200 ml of ice water and extracted with ether. The organic layer is washed with water, dried and concentrated. The oily residue is dissolved in 20 ml of ethanol. The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate. The white crystals deposited are separated by filtration, washed with 20 ml of ethyl acetate and dried to obtain 5.70 g of a crude product. The crude product is recrystallized from hot ethanol to obtain 2.90 g of the desired product. stirred is brought back to room temperature stirred at room temperature for 2 hours extracted with ether The organic layer is washed with water dried concentrated The oily residue is dissolved in 20 ml of ethanol The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate The white crystals deposited are separated by filtration washed with 20 ml of ethyl acetate dried to obtain 5.70 g of a crude product The crude product is recrystallized from hot ethanol

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

Procedure: In this reference example, 5.24 g of 1-benzyl-4-amino-piperidine dihydrochloride, 3.02 g of o-nitrobenzaldehyde, 2.02 g of triethylamine and 30 ml of methanol are mixed and stirred at room temperature for one hour. The resultant solution is cooled with ice and stirred. To the stirred solution, 1 g of sodium borohydride is added little by little over a period of one hour. Then, the mixture is brought back to room temperature and stirred at room temperature for 2 hours. The resultant solution is poured into 200 ml of ice water and extracted with ether. The organic layer is washed with water, dried and concentrated. The oily residue is dissolved in 20 ml of ethanol. The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate. The white crystals deposited are separated by filtration, washed with 20 ml of ethyl acetate and dried to obtain 5.70 g of a crude product. The crude product is recrystallized from hot ethanol to obtain 2.90 g of the desired product. stirred is brought back to room temperature stirred at room temperature for 2 hours extracted with ether The organic layer is washed with water dried concentrated The oily residue is dissolved in 20 ml of ethanol The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate The white crystals deposited are separated by filtration washed with 20 ml of ethyl acetate dried to obtain 5.70 g of a crude product The crude product is recrystallized from hot ethanol

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

Procedure: In this reference example, 5.24 g of 1-benzyl-4-amino-piperidine dihydrochloride, 3.02 g of o-nitrobenzaldehyde, 2.02 g of triethylamine and 30 ml of methanol are mixed and stirred at room temperature for one hour. The resultant solution is cooled with ice and stirred. To the stirred solution, 1 g of sodium borohydride is added little by little over a period of one hour. Then, the mixture is brought back to room temperature and stirred at room temperature for 2 hours. The resultant solution is poured into 200 ml of ice water and extracted with ether. The organic layer is washed with water, dried and concentrated. The oily residue is dissolved in 20 ml of ethanol. The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate. The white crystals deposited are separated by filtration, washed with 20 ml of ethyl acetate and dried to obtain 5.70 g of a crude product. The crude product is recrystallized from hot ethanol to obtain 2.90 g of the desired product. stirred is brought back to room temperature stirred at room temperature for 2 hours extracted with ether The organic layer is washed with water dried concentrated The oily residue is dissolved in 20 ml of ethanol The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate The white crystals deposited are separated by filtration washed with 20 ml of ethyl acetate dried to obtain 5.70 g of a crude product The crude product is recrystallized from hot ethanol

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

Procedure: In this reference example, 5.24 g of 1-benzyl-4-amino-piperidine dihydrochloride, 3.02 g of o-nitrobenzaldehyde, 2.02 g of triethylamine and 30 ml of methanol are mixed and stirred at room temperature for one hour. The resultant solution is cooled with ice and stirred. To the stirred solution, 1 g of sodium borohydride is added little by little over a period of one hour. Then, the mixture is brought back to room temperature and stirred at room temperature for 2 hours. The resultant solution is poured into 200 ml of ice water and extracted with ether. The organic layer is washed with water, dried and concentrated. The oily residue is dissolved in 20 ml of ethanol. The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate. The white crystals deposited are separated by filtration, washed with 20 ml of ethyl acetate and dried to obtain 5.70 g of a crude product. The crude product is recrystallized from hot ethanol to obtain 2.90 g of the desired product. stirred is brought back to room temperature stirred at room temperature for 2 hours extracted with ether The organic layer is washed with water dried concentrated The oily residue is dissolved in 20 ml of ethanol The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate The white crystals deposited are separated by filtration washed with 20 ml of ethyl acetate dried to obtain 5.70 g of a crude product The crude product is recrystallized from hot ethanol

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

Procedure: A solution of (R)-tetrahydro-2-furoic acid (58.5 g, 504 mmol) and oxalyl chloride (86 mL, 1.0 mol) in 100 mL CH2Cl2 were refluxed for 2 hours in a flask equipped with a CaCl2 guard tube. After the solution was cooled to room temperature the solvents and excess oxalyl chloride were removed by evaporation under reduced pressure. The resulting acid chloride was dissolved in 200 mL CH2Cl2 and added dropwise to a solution of 1-benzyl-4-amino piperidine dihydrochloride (142 g, 539 mmol) and triethylamine (240 mL, 1.7 mol) in 300 mL CH2Cl2 cooled in an ice bath. The resulting mixture was stirred for 2 hours at room temperature and subsequently washed twice with 300 mL portions of 5% aq. NaHCO3 and 300 mL saturated aq. NaCl solution, dried over Na2SO4, filtered, and evaporated to dryness under reduced pressure. The solid residue was triturated with 500 mL heptanes, collected by filtration, and washed twice with 200 mL portions of heptanes. The solid was air-dried at 45° C. to yield (R)-tetrahydrofuran-2-carboxylic acid (1-benzyl-piperidin-4-yl)-amide (128 g, 88%) as an off-white solid. 1H-NMR (300 MHz, CDCl3): δ 7.35-7.20 (m, 5H), 6.58 (bs, 1H), 4.29 (dd, J=5.9, 8.4 Hz, 1H), 3.92-3.77 (m, 2H), 3.48 (s, 2H), 2.82-2.74 (m, 2H), 2.32-2.21 (m, 1H), 2.19-1.95 (m, 3H), 1.94-1.78 (m, 4H), 1.58-1.40 (m, 2H) ppm. equipped with a CaCl2 guard tube were removed by evaporation under reduced pressure The resulting acid chloride was dissolved in 200 mL CH2Cl2 cooled in an ice bath subsequently washed twice with 300 mL portions of 5% aq. NaHCO3 and 300 mL saturated aq. NaCl solution dried over Na2SO4 filtered evaporated to dryness under reduced pressure The solid residue was triturated with 500 mL heptanes collected by filtration washed twice with 200 mL portions of heptanes The solid was air-dried at 45° C.

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

Procedure: A solution of (R)-tetrahydro-2-furoic acid (58.5 g, 504 mmol) and oxalyl chloride (86 mL, 1.0 mol) in 100 mL CH2Cl2 were refluxed for 2 hours in a flask equipped with a CaCl2 guard tube. After the solution was cooled to room temperature the solvents and excess oxalyl chloride were removed by evaporation under reduced pressure. The resulting acid chloride was dissolved in 200 mL CH2Cl2 and added dropwise to a solution of 1-benzyl-4-amino piperidine dihydrochloride (142 g, 539 mmol) and triethylamine (240 mL, 1.7 mol) in 300 mL CH2Cl2 cooled in an ice bath. The resulting mixture was stirred for 2 hours at room temperature and subsequently washed twice with 300 mL portions of 5% aq. NaHCO3 and 300 mL saturated aq. NaCl solution, dried over Na2SO4, filtered, and evaporated to dryness under reduced pressure. The solid residue was triturated with 500 mL heptanes, collected by filtration, and washed twice with 200 mL portions of heptanes. The solid was air-dried at 45° C. to yield (R)-tetrahydrofuran-2-carboxylic acid (1-benzyl-piperidin-4-yl)-amide (128 g, 88%) as an off-white solid. 1H-NMR (300 MHz, CDCl3): δ 7.35-7.20 (m, 5H), 6.58 (bs, 1H), 4.29 (dd, J=5.9, 8.4 Hz, 1H), 3.92-3.77 (m, 2H), 3.48 (s, 2H), 2.82-2.74 (m, 2H), 2.32-2.21 (m, 1H), 2.19-1.95 (m, 3H), 1.94-1.78 (m, 4H), 1.58-1.40 (m, 2H) ppm. equipped with a CaCl2 guard tube were removed by evaporation under reduced pressure The resulting acid chloride was dissolved in 200 mL CH2Cl2 cooled in an ice bath subsequently washed twice with 300 mL portions of 5% aq. NaHCO3 and 300 mL saturated aq. NaCl solution dried over Na2SO4 filtered evaporated to dryness under reduced pressure The solid residue was triturated with 500 mL heptanes collected by filtration washed twice with 200 mL portions of heptanes The solid was air-dried at 45° C.

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

Procedure: In this reference example, 5.24 g of 1-benzyl-4-amino-piperidine dihydrochloride, 3.02 g of o-nitrobenzaldehyde, 2.02 g of triethylamine and 30 ml of methanol are mixed and stirred at room temperature for one hour. The resultant solution is cooled with ice and stirred. To the stirred solution, 1 g of sodium borohydride is added little by little over a period of one hour. Then, the mixture is brought back to room temperature and stirred at room temperature for 2 hours. The resultant solution is poured into 200 ml of ice water and extracted with ether. The organic layer is washed with water, dried and concentrated. The oily residue is dissolved in 20 ml of ethanol. The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate. The white crystals deposited are separated by filtration, washed with 20 ml of ethyl acetate and dried to obtain 5.70 g of a crude product. The crude product is recrystallized from hot ethanol to obtain 2.90 g of the desired product. stirred is brought back to room temperature stirred at room temperature for 2 hours extracted with ether The organic layer is washed with water dried concentrated The oily residue is dissolved in 20 ml of ethanol The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate The white crystals deposited are separated by filtration washed with 20 ml of ethyl acetate dried to obtain 5.70 g of a crude product The crude product is recrystallized from hot ethanol

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

Procedure: In this reference example, 5.24 g of 1-benzyl-4-amino-piperidine dihydrochloride, 3.02 g of o-nitrobenzaldehyde, 2.02 g of triethylamine and 30 ml of methanol are mixed and stirred at room temperature for one hour. The resultant solution is cooled with ice and stirred. To the stirred solution, 1 g of sodium borohydride is added little by little over a period of one hour. Then, the mixture is brought back to room temperature and stirred at room temperature for 2 hours. The resultant solution is poured into 200 ml of ice water and extracted with ether. The organic layer is washed with water, dried and concentrated. The oily residue is dissolved in 20 ml of ethanol. The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate. The white crystals deposited are separated by filtration, washed with 20 ml of ethyl acetate and dried to obtain 5.70 g of a crude product. The crude product is recrystallized from hot ethanol to obtain 2.90 g of the desired product. stirred is brought back to room temperature stirred at room temperature for 2 hours extracted with ether The organic layer is washed with water dried concentrated The oily residue is dissolved in 20 ml of ethanol The solution is mixed with 10 ml of a solution of 5.7 N hydrochloric acid in ethyl acetate The white crystals deposited are separated by filtration washed with 20 ml of ethyl acetate dried to obtain 5.70 g of a crude product The crude product is recrystallized from hot ethanol