ethyl 4-(hydroxymethyl)piperidine-1-carboxylate

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: A solution of 1.2 eq oxalyl chloride (12.69 g, 0.10 mol) in dichloromethane (150 mL) was cooled to approximately −78° C. and treated dropwise, under nitrogen, with a solution of 2.4 eq anhydrous dimethylsulfoxide (15.63 g, 0.20 mol) in dichloromethane (50 mL). 15 minutes after the addition was complete, a solution of 1.0 eq ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate (15.60 g, 83.3 mmol) in dichloromethane (50 mL) was added dropwise. 30 minutes after the addition was complete, a solution of 3.0 eq triethylamine (25.30 g, 0.25 mol) in dichloromethane (50 mL) was added dropwise and the reaction warmed to room temperature. The reaction was stirred at room temperature for 1 hour, then quenched with saturated sodium bicarbonate (500 mL). The layers were separated and the aqueous layer extracted once with dichloromethane (200 mL). The pooled organic layers were washed with H2O (3×100 mL), saturated sodium bicarbonate (1×100 mL) and saturated brine, then dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to afford 13.84 g ethyl 4-formylpiperidine-1-carboxylate as a viscous amber oil. 1H-NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 4.10 (q, J=7.2 Hz, 2H), 4.00 (br m, 2H), 2.97 (m, 2H), 2.40 (m, 1H), 1.87 (br m, 2H), 1.54 (m, 2H), 1.23 (t, J=7.0 Hz, 3H). 15 minutes after the addition 30 minutes after the addition quenched with saturated sodium bicarbonate (500 mL) The layers were separated the aqueous layer extracted once with dichloromethane (200 mL) The pooled organic layers were washed with H2O (3×100 mL), saturated sodium bicarbonate (1×100 mL) and saturated brine dried (Na2SO4) filtered The filtrate was concentrated in vacuo

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

Procedure: 1.0 eq 4-piperidinemethanol (10.00 g, 86.8 mmol) was dissolved in dichloromethane (350 mL), cooled in an ice-H2O bath and treated dropwise with a solution of 1.05 eq ethyl chloroformate (9.89 g, 91.1 mmol) in dichloromethane (50 mL), followed by the dropwise addition of a solution of 1.0 eq triethylamine (8.78 g) in dichloromethane (50 mL). The reaction was stirred at −0° C. for 15 minutes, then at room temperature for 10 minutes. The reaction was diluted with dichloromethane (250 mL) and washed successively with (150 mL each) H2O, 0.1 N HCl (aq) (×2), saturated brine, then dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to afford 15.60 g ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate as a viscous, pale bluish-green oil. 1H-NMR (400 MHz, CDCl3) δ 4.15 (br m, 2H), 4.09 (q,J=7.1 Hz, 2H), 3.46 (d, J=6.4 Hz, 2H), 2.72 (br t, J=12.4 Hz, 2H), 2.07 (s, 1H), 1.70 (m, 2H), 1.63 (m, 1H), 1.23 (t, J=7.2 Hz, 3H), 1.12 (m, 2H); tR=1.56 min [10-99% CH3CN gradient over 5 mins with 0.1% TFA (aq)]; Theoretical (M+H)+ m/z for C9H17NO3=188.1; Found 188.0. cooled in an ice-H2O bath at room temperature for 10 minutes washed successively with (150 mL each) H2O, 0.1 N HCl (aq) (×2), saturated brine dried (Na2SO4) filtered The filtrate was concentrated in vacuo

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

Procedure: A solution of 1.2 eq oxalyl chloride (12.69 g, 0.10 mol) in dichloromethane (150 mL) was cooled to approximately −78° C. and treated dropwise, under nitrogen, with a solution of 2.4 eq anhydrous dimethylsulfoxide (15.63 g, 0.20 mol) in dichloromethane (50 mL). 15 minutes after the addition was complete, a solution of 1.0 eq ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate (15.60 g, 83.3 mmol) in dichloromethane (50 mL) was added dropwise. 30 minutes after the addition was complete, a solution of 3.0 eq triethylamine (25.30 g, 0.25 mol) in dichloromethane (50 mL) was added dropwise and the reaction warmed to room temperature. The reaction was stirred at room temperature for 1 hour, then quenched with saturated sodium bicarbonate (500 mL). The layers were separated and the aqueous layer extracted once with dichloromethane (200 mL). The pooled organic layers were washed with H2O (3×100 mL), saturated sodium bicarbonate (1×100 mL) and saturated brine, then dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to afford 13.84 g ethyl 4-formylpiperidine-1-carboxylate as a viscous amber oil. 1H-NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 4.10 (q, J=7.2 Hz, 2H), 4.00 (br m, 2H), 2.97 (m, 2H), 2.40 (m, 1H), 1.87 (br m, 2H), 1.54 (m, 2H), 1.23 (t, J=7.0 Hz, 3H). 15 minutes after the addition 30 minutes after the addition quenched with saturated sodium bicarbonate (500 mL) The layers were separated the aqueous layer extracted once with dichloromethane (200 mL) The pooled organic layers were washed with H2O (3×100 mL), saturated sodium bicarbonate (1×100 mL) and saturated brine dried (Na2SO4) filtered The filtrate was concentrated in vacuo

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

Procedure: A solution of 1.2 eq oxalyl chloride (12.69 g, 0.10 mol) in dichloromethane (150 mL) was cooled to approximately −78° C. and treated dropwise, under nitrogen, with a solution of 2.4 eq anhydrous dimethylsulfoxide (15.63 g, 0.20 mol) in dichloromethane (50 mL). 15 minutes after the addition was complete, a solution of 1.0 eq ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate (15.60 g, 83.3 mmol) in dichloromethane (50 mL) was added dropwise. 30 minutes after the addition was complete, a solution of 3.0 eq triethylamine (25.30 g, 0.25 mol) in dichloromethane (50 mL) was added dropwise and the reaction warmed to room temperature. The reaction was stirred at room temperature for 1 hour, then quenched with saturated sodium bicarbonate (500 mL). The layers were separated and the aqueous layer extracted once with dichloromethane (200 mL). The pooled organic layers were washed with H2O (3×100 mL), saturated sodium bicarbonate (1×100 mL) and saturated brine, then dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to afford 13.84 g ethyl 4-formylpiperidine-1-carboxylate as a viscous amber oil. 1H-NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 4.10 (q, J=7.2 Hz, 2H), 4.00 (br m, 2H), 2.97 (m, 2H), 2.40 (m, 1H), 1.87 (br m, 2H), 1.54 (m, 2H), 1.23 (t, J=7.0 Hz, 3H). 15 minutes after the addition 30 minutes after the addition quenched with saturated sodium bicarbonate (500 mL) The layers were separated the aqueous layer extracted once with dichloromethane (200 mL) The pooled organic layers were washed with H2O (3×100 mL), saturated sodium bicarbonate (1×100 mL) and saturated brine dried (Na2SO4) filtered The filtrate was concentrated in vacuo

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

Procedure: 1.0 eq 4-piperidinemethanol (10.00 g, 86.8 mmol) was dissolved in dichloromethane (350 mL), cooled in an ice-H2O bath and treated dropwise with a solution of 1.05 eq ethyl chloroformate (9.89 g, 91.1 mmol) in dichloromethane (50 mL), followed by the dropwise addition of a solution of 1.0 eq triethylamine (8.78 g) in dichloromethane (50 mL). The reaction was stirred at ≈0° C. for 15 minutes, then at room temperature for 10 minutes. The reaction was diluted with dichloromethane (250 mL) and washed successively with (150 mL each) H2O, 0.1 N HCl (aq) (×2), saturated brine, then dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to afford 15.60 g ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate as a viscous, pale bluish-green oil. 1H-NMR (400 MHz, CDCl3) δ 4.15 (br m, 2H), 4.09 (q, J=7.1 Hz, 2H), 3.46 (d, J=6.4 Hz, 2H), 2.72 (br t, J=12.4 Hz, 2H), 2.07 (s, 1H), 1.70 (m, 2H), 1.63 (m, 1H), 1.23 (t, J=7.2 Hz, 3H), 1.12 (m, 2H); LC/MS [M+H]+ m/z 188.0, retention time 1.56 min (10-99% CH3CN—H2O gradient, with 0.1% TFA, 5 min). cooled in an ice-H2O bath at room temperature for 10 minutes washed successively with (150 mL each) H2O, 0.1 N HCl (aq) (×2), saturated brine dried (Na2SO4) filtered The filtrate was concentrated in vacuo

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

Procedure: 1.0 eq 4-piperidinemethanol (10.00 g, 86.8 mmol) was dissolved in dichloromethane (350 mL), cooled in an ice-H2O bath and treated dropwise with a solution of 1.05 eq ethyl chloroformate (9.89 g, 91.1 mmol) in dichloromethane (50 mL), followed by the dropwise addition of a solution of 1.0 eq triethylamine (8.78 g) in dichloromethane (50 mL). The reaction was stirred at ≈0° C. for 15 minutes, then at room temperature for 10 minutes. The reaction was diluted with dichloromethane (250 mL) and washed successively with (150 mL each) H2O, 0.1 N HCl (aq) (×2), saturated brine, then dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to afford 15.60 g ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate as a viscous, pale bluish-green oil. 1H-NMR (400 MHz, CDCl3) δ 4.15 (br m, 2H), 4.09 (q, J=7.1 Hz, 2H), 3.46 (d, J=6.4 Hz, 2H), 2.72 (br t, J=12.4 Hz, 2H), 2.07 (s, 1H), 1.70 (m, 2H), 1.63 (m, 1H), 1.23 (t, J=7.2 Hz, 3H), 1.12 (m, 2H); LC/MS [M+H]+ m/z 188.0, retention time 1.56 min (10-99% CH3CN—H2O gradient, with 0.1% TFA, 5 min). cooled in an ice-H2O bath at room temperature for 10 minutes washed successively with (150 mL each) H2O, 0.1 N HCl (aq) (×2), saturated brine dried (Na2SO4) filtered The filtrate was concentrated in vacuo

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

Procedure: A solution of 0.67 g of ethyl chloroformate in 2 ml of tetrahydrofuran was added to a solution of 1.01 g of ethyl 4-carboxypiperidine-1-carboxylate and 0.72 g of triethylamine in 20 ml of tetrahydrofuran at -10° to -5° C., and the mixture was stirred for 30 minutes. The resultant crystalline precipitate was filtered off, the filtrate was added to a solution of 0.57 g of sodium borohydride in 10 ml of water with ice cooling over 30 minutes, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was made acidic with 1N hydrochloric acid with ice cooling and then extracted with ether. The ether layer was washed in sequence with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. Elution with a hexane-ethyl acetate (1:1 v/v) mixture gave 0.69 g of ethyl 4-hydroxymethylpiperidine-1-carboxylate The resultant crystalline precipitate was filtered off the filtrate was added to a solution of 0.57 g of sodium borohydride in 10 ml of water with ice cooling over 30 minutes the mixture was stirred at room temperature for 30 minutes extracted with ether The ether layer was washed in sequence with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride dried over anhydrous magnesium sulfate concentrated under reduced pressure Elution with a hexane-ethyl acetate (1:1 v/v) mixture

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

Procedure: A solution of oxalyl chloride (12.69 g, 0.10 mol) in dichloromethane (150 mL) was cooled to approximately −78° C. and treated dropwise under nitrogen with a solution of anhydrous dimethylsulfoxide (15.63 g, 0.20 mol) in dichloromethane (50 mL). 15 min after the addition was complete, a solution of ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate (15.60 g, 83.3 mmol) (B2) in dichloromethane (50 mL) was added dropwise. 30 minutes after the addition was complete, a solution of triethylamine (25.30 g, 0.25 mol) in dichloromethane (50 mL) was added dropwise and the reaction warmed to room temperature. The reaction was stirred at room temperature for 1 hour, then quenched with saturated sodium bicarbonate (500 mL). The layers were separated and the aqueous layer extracted once with dichloromethane (200 mL). The pooled organic layers were washed with water (3×100 mL), saturated sodium bicarbonate (1×100 mL) and saturated brine (1×100 mL), then dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford ethyl 4-formylpiperidine-1-carboxylate (B3) as a viscous amber oil. 1H-NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 4.10 (q, J=7.2 Hz, 2H), 4.00 (br m, 2H), 2.97 (m, 2H), 2.40 (m, 1H), 1.87 (br m, 2H), 1.54 (m, 2H), 1.23 (t, J=7.0 Hz, 3H). 15 min after the addition 30 minutes after the addition quenched with saturated sodium bicarbonate (500 mL) The layers were separated the aqueous layer extracted once with dichloromethane (200 mL) The pooled organic layers were washed with water (3×100 mL), saturated sodium bicarbonate (1×100 mL) and saturated brine (1×100 mL) dried over Na2SO4 filtered The filtrate was concentrated in vacuo

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

Procedure: 4-piperidinemethanol (10.00 g, 86.8 mmol) (B1) was dissolved in dichloromethane (350 mL), cooled in an ice water bath and treated dropwise with a solution of ethyl chloroformate (9.89 g, 91.1 mmol) in dichloromethane (50 mL), followed by the dropwise addition of a solution of triethylamine (8.78 g) in dichloromethane (50 mL). The reaction was stirred at 0° C. for 15 min, then at room temperature for 10 min. The reaction was diluted with dichloromethane (250 mL) and washed successively with water (2×150 mL), 0.1 N HCl (2×150 mL), saturated brine (2×150 mL), then dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford ethyl 4-(hydroxymethyl)-piperidine-1-carboxylate (B2) as a viscous, pale bluish-green oil (15.60 g, 96% yield). 1H-NMR (400 MHz, CDCl3) δ 4.15 (br m, 2H), 4.09 (q, J=7.1 Hz, 2H), 3.46 (d, J=6.4 Hz, 2H), 2.72 (br t, J=12.4 Hz, 2H), 2.07 (s, 1H), 1.70 (m, 2H), 1.63 (m, 1H), 1.23 (t, J=7.2 Hz, 3H), 1.12 (m, 2H); LC/MS m/z 188.0 [M+H]+, retention time 1.56 min (RP-C18, 10-99% CH3CN/0.05% TFA). cooled in an ice water bath at room temperature for 10 min washed successively with water (2×150 mL), 0.1 N HCl (2×150 mL), saturated brine (2×150 mL) dried over Na2SO4 filtered The filtrate was concentrated in vacuo