ethyl 2-oxopiperidine-3-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:

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

Procedure: 3-Carbethoxy-2-piperidone (4.7 g, 27.4 mmol) is stirred with potassium hydroxide (1.64 g) in water (56 mL) and kept at 30° C. on an oil bath overnight. 3-Bromoaniline (4.99 g, 29 mmol) is treated with water (50 mL) and concentrated HCl (10 mL) and cooled to 0° C. Sodium nitrite (2.46 g, 35 mmol) in water (9 mL) is added dropwise to the above solution at 0° C. and stirred for an additional 20 minutes. Urea is added to decompose the excess nitrous acid, and the diazotized solution is neutralized with 10% aqueous sodium carbonate solution (45-50 mL). The resulting solution is filtered into the solution of previously hydrolyzed 3-carbethoxy-2-piperidone (2-piperidone-3-carboxylic acid) at 0° C. After a few minutes, glacial acetic acid is added to bring the pH of the solution to 3-4. The reaction mixture is stirred at 0° C. for 5-6 h, and the yellow precipitate which resulted is filtered, washed with water, and dried to get the title compound (2.5 g, 32% yield). The resulting solution is filtered into the solution of previously hydrolyzed 3-carbethoxy-2-piperidone (2-piperidone-3-carboxylic acid) at 0° C After a few minutes glacial acetic acid is added The reaction mixture is stirred at 0° C. for 5-6 h the yellow precipitate which resulted is filtered washed with water dried

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

Procedure: 3-Carbethoxy-2-piperidone (4.7 g, 27.4 mmol) is stirred with potassium hydroxide (1.64 g) in water (56 mL) and kept at 30° C. on an oil bath overnight. 3-Bromoaniline (4.99 g, 29 mmol) is treated with water (50 mL) and concentrated HCl (10 mL) and cooled to 0° C. Sodium nitrite (2.46 g, 35 mmol) in water (9 mL) is added dropwise to the above solution at 0° C. and stirred for an additional 20 minutes. Urea is added to decompose the excess nitrous acid, and the diazotized solution is neutralized with 10% aqueous sodium carbonate solution (45-50 mL). The resulting solution is filtered into the solution of previously hydrolyzed 3-carbethoxy-2-piperidone (2-piperidone-3-carboxylic acid) at 0° C. After a few minutes, glacial acetic acid is added to bring the pH of the solution to 3-4. The reaction mixture is stirred at 0° C. for 5-6 h, and the yellow precipitate which resulted is filtered, washed with water, and dried to get the title compound (2.5 g, 32% yield). The resulting solution is filtered into the solution of previously hydrolyzed 3-carbethoxy-2-piperidone (2-piperidone-3-carboxylic acid) at 0° C After a few minutes glacial acetic acid is added The reaction mixture is stirred at 0° C. for 5-6 h the yellow precipitate which resulted is filtered washed with water dried

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

Procedure: The title compound was prepared analogous to 3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole from ethyl 2-oxopiperidine-3-carboxylate (2.57 g, 15 mmol), Me3OBF4 (2.66 g, 18 mmol) and isonicotinic hydrazide (2.06 g, 15 mmol) in DCM (150 ml) and EtOH (16 ml). Recrystallization from EA afforded 1.67 g (41%). 1H NMR: 1.29 (t, 3 H), 2.03 (m, 1 H), 2.14-2.25 (m, 2 H), 2.32 (m, 1 H), 4.01-4.12 (m, 1 H), 4.16-4.27 (m, 4 H), 7.64 (d, 2 H), 8.74 (d, 2 H) Recrystallization from EA afforded 1.67 g (41%)

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

Procedure: The title compound was prepared analogous to 3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole from ethyl 2-oxopiperidine-3-carboxylate (2.57 g, 15 mmol), Me3OBF4 (2.66 g, 18 mmol) and isonicotinic hydrazide (2.06 g, 15 mmol) in DCM (150 ml) and EtOH (16 ml). Recrystallization from EA afforded 1.67 g (41%). 1H NMR: 1.29 (t, 3 H), 2.03 (m, 1 H), 2.14-2.25 (m, 2 H), 2.32 (m, 1 H), 4.01-4.12 (m, 1 H), 4.16-4.27 (m, 4 H), 7.64 (d, 2 H), 8.74 (d, 2 H) Recrystallization from EA afforded 1.67 g (41%)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 5 mmol of 2-oxo-piperidine-3-carboxylic acid ethyl ester [3731-16-6] in 30 ml dry of tetrahydrofuran is added dropwise 5.25 mmol of an n-butyl lithium solution (1.6M in hexane) at −78° C. After stirring for 15 minutes at −78° C., trimethylsilyl chloride (0.67 mL, 5.25 mmol) is added dropwise and stirring is continued for 30 minutes while the solution is allowed to warm to 0° C. The reaction mixture is then cooled to −78° C. and transferred (via cannula) to a solution of 5 mmol of freshly prepared lithium diisopropyl-amide in 20 ml of dry tetrahydrofuran at −78° C. After stirring for 30 minutes at −78° C., 5.25 mmol of 2-bromoacetic acid ethyl ester [105-36-2] are added drop wise and stirring is continued for 1 hour while the solution is allowed to warm to 0° C. The reaction is quenched by addition of aqueous saturated ammonium chloride solution and extracted with diethyl ether (3×). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value. stirring is continued for 30 minutes while the solution to warm to 0° C The reaction mixture is then cooled to −78° C. at −78° C After stirring for 30 minutes at −78° C. stirring is continued for 1 hour while the solution to warm to 0° C The reaction is quenched by addition of aqueous saturated ammonium chloride solution extracted with diethyl ether (3×) The combined organic phases are washed with brine dried with sodium sulphate evaporated

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Dimethylaminopyridine (0.35 wt), (+)-menthol (0.95 wt) and ethyl 2-oxo-3-piperidinecarboxylate (1 wt) are dissolved/suspended in toluene (10 vol). The mixture is heated to reflux and stirred for seven days with periodic distillation of solvent and replenishment with fresh toluene. The reaction mixture is cooled to 25° C. and washed with two portions of 5% w/w aqueous HCl (4 vol) and then water (4 vol). The organic phase is concentrated under reduced pressure to give the title compound as a colourless oil. The mixture is heated to reflux washed with two portions of 5% w/w aqueous HCl (4 vol) The organic phase is concentrated under reduced pressure

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Dimethylaminopyridine (0.35 wt), (+)-menthol (0.95 wt) and ethyl 2-oxo-3-piperidinecarboxylate (1 wt) are dissolved/suspended in toluene (10 vol). The mixture is heated to reflux and stirred for seven days with periodic distillation of solvent and replenishment with fresh toluene. The reaction mixture is cooled to 25° C. and washed with two portions of 5% w/w aqueous HCl (4 vol) and then water (4 vol). The organic phase is concentrated under reduced pressure to give the title compound as a colourless oil. The mixture is heated to reflux washed with two portions of 5% w/w aqueous HCl (4 vol) The organic phase is concentrated under reduced pressure

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