4-(aminomethyl)-1-benzylpiperidin-4-ol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of 4-aminomethyl-1-benzyl-piperidin-4-ol (264 mmol, 58 g) in DCM (200 mL) and saturated NaHCO3 (200 mL) was added di-tert-butylcarbonate (396 mmol, 86.4 g). The reaction mixture was stirred for 12 hours. The layers were separated and the organic layer was washed with brine (50 mL) and evaporated. The product was purified on 1 L of SiO2 using a mixtures of ethyl acetate and DCM to give (1-benzyl-4-hydroxy-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester (31 g). The layers were separated the organic layer was washed with brine (50 mL) evaporated The product was purified on 1 L of SiO2 using a mixtures of ethyl acetate and DCM

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of compound 397 (39.7 g, 180 mmol) in dichloromethane (350 mL) was added triethylamine (50.0 mL, 359 mmol), followed by dropwise addition of chloroacetyl chloride (16.5 mL, 207 mmol) over 15 minutes. The resulting solution was stirred at room temperature for 1.25 hours. The crude mixture was diluted with DCM and water, and extracted with DCM twice. The combined organics were dried over Na2SO4 and concentrated in vacuo to give compound 398 (41.9 g, 78%). LCMS-ESI (POS), M/Z, M+1: Found 297.1, Calculated 297.1. extracted with DCM twice The combined organics were dried over Na2SO4 concentrated in vacuo

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

Procedure: To a pre-cooled solution (20° C.) of 1-benzyl-4-piperidone (35.0 mL, 196 mmol) and triethylamine (5.5 mL, 40 mmol) was added trimethylsilylcyanide (32.0 mL, 240 mmol), portionwise over 10 minutes. Once the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. This reaction mixture was then cautiously added (10 mL portions over 12 minutes) to a stirring mixture of lithium aluminum hydride (8.5 g, 224 mmol) in tetrahydrofuran (420 mL). Once the addition was complete the reaction mixture was refluxed for 1.5 hours. After cooling to room temperature, the reaction was quenched with water (8.5 mL), followed by 1N NaOH (8.5 mL), and then water (2×8.5 mL). The resulting mixture was allowed to stir at room temperature overnight. The solids were filtered off and rinsed with DCM and ethanol. The filtrate was concentrated down to a solid and then purified by flash chromatography (0-20% methanol in DCM with 1% NH4OH) to give compound 397 as a yellow solid (39.7 g, 92%). LCMS-ESI (POS), M/Z, M+1: Found 221.2, Calculated 221.2. Once the addition This reaction mixture was then cautiously added (10 mL portions over 12 minutes) Once the addition was refluxed for 1.5 hours After cooling to room temperature the reaction was quenched with water (8.5 mL) to stir at room temperature overnight The solids were filtered off rinsed with DCM and ethanol The filtrate was concentrated down to a solid purified by flash chromatography (0-20% methanol in DCM with 1% NH4OH)

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

Procedure: To a solution of crude 1-benzyl-4-hydroxy-4-aminomethyl piperidine, as described above in Step A, (˜3.1 gm, 12 mmol) in acetonitrile (50 mL) containing triethyl amine (5.7 mL, 42 mmol) cooled in an ice bath was added in 1 mL portions 20% phosgene/toluene (9 mL) over a three hour period. The reaction mixture was stirred at ambient temp. for 15 hours and diluted with ethyl acetate. This solution was washed with water (2×) and the organic layer dried (anhyd. sodium sulfate), filtered, and the solvent removed under vacuum. The residue was triturated with diethyl ether and the title compound collected by filtration as a white solid, mp: 159-161° C. cooled in an ice bath This solution was washed with water (2×) the organic layer dried (anhyd. sodium sulfate) filtered the solvent removed under vacuum The residue was triturated with diethyl ether the title compound collected by filtration as a white solid, mp: 159-161° C.

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

Procedure: To a solution of crude 1-benzyl-4-hydroxy-4-aminomethyl piperidine, as described above in Step A, (˜3.1 gm, 12 mmol) in acetonitrile (50 mL) containing triethyl amine (5.7 mL, 42 mmol) cooled in an ice bath was added in 1 mL portions 20% phosgene/toluene (9 mL) over a three hour period. The reaction mixture was stirred at ambient temp. for 15 hours and diluted with ethyl acetate. This solution was washed with water (2×) and the organic layer dried (anhyd. sodium sulfate), filtered, and the solvent removed under vacuum. The residue was triturated with diethyl ether and the title compound collected by filtration as a white solid, mp: 159-161° C. cooled in an ice bath This solution was washed with water (2×) the organic layer dried (anhyd. sodium sulfate) filtered the solvent removed under vacuum The residue was triturated with diethyl ether the title compound collected by filtration as a white solid, mp: 159-161° C.

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

Procedure: To neat 1-benzyl-4-piperidone (2.22 mL, 12 mmol) was added trimethylsilyl cyanide (1.95 mL, ˜15 mmol) and zinc iodide (˜5 mg). The solution was stirred for 6 hours or until reaction was completed as indicated by tlc. This oil was dissolved in diethyl ether (30 mL), filtered to remove some solid and added dropwise to a solution of diethyl ether (15 mL) containing 1M lithium aluminium hydride/diethyl ether (30 mL). After stirring at ambient temp. for 2 hours, the reaction was carefully quenched with aqueous sat'd sodium sulfate. This suspension was diluted with more diethyl ether, filtered to remove solids, and the solvent evaporated under partial vacuum to give the crude title compound as an oil. filtered to remove some solid added dropwise to a solution of diethyl ether (15 mL) containing 1M lithium aluminium hydride/diethyl ether (30 mL) After stirring at ambient temp. for 2 hours the reaction was carefully quenched with aqueous sat'd sodium sulfate This suspension was diluted with more diethyl ether filtered to remove solids the solvent evaporated under partial vacuum