ethyl 3-[(3-ethoxy-3-oxopropyl)-methylamino]-3-oxopropanoate

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 50-mL round bottomed flask was added ethanol (4 mL) under argon, followed by sodium (0.121 g, 5.25 mmol). The mixture was stirred at room temperature for 15 min, during which a solution of ethyl 3-((3-ethoxy-3-oxopropyl)(methyl)amino)-3-oxopropanoate (1.17 g, 4.77 mmol) in ethanol (5 mL) was added. The resulting clear, colorless mixture was heated at 80° C. for 1 h, during which LC-MS indicated completion of reaction and a clean conversion to the desired ethyl 1-methyl-2,4-dioxopiperidine-3-carboxylate intermediate. Upon cooling to room temperature, the reaction was diluted with Et2O, resulting in the formation of a white precipitate (desired product). The white precipitate was collected via filtration, taken up in 5% aqueous HCl solution (8 mL), and refluxed for 1 h. The cooled mixture was extracted with CH2Cl2 (5×) and the combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% EtOAc/Hexanes to 100% EtOAc) afforded 1-methylpiperidine-2,4-dione as a viscous milky oil. [M+1]=128.1. was added completion of reaction Upon cooling to room temperature

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 50-mL round bottomed flask was added ethanol (4 mL) under argon, followed by sodium (0.121 g, 5.25 mmol). The mixture was stirred at room temperature for 15 min, during which a solution of ethyl 3-((3-ethoxy-3-oxopropyl)(methyl)amino)-3-oxopropanoate (1.17 g, 4.77 mmol) in ethanol (5 mL) was added. The resulting clear, colorless mixture was heated at 80° C. for 1 h, during which LC-MS indicated completion of reaction and a clean conversion to the desired ethyl 1-methyl-2,4-dioxopiperidine-3-carboxylate intermediate. Upon cooling to room temperature, the reaction was diluted with Et2O, resulting in the formation of a white precipitate (desired product). The white precipitate was collected via filtration, taken up in 5% aqueous HCl solution (8 mL), and refluxed for 1 h. The cooled mixture was extracted with CH2Cl2 (5×) and the combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% EtOAc/Hexanes to 100% EtOAc) afforded 1-methylpiperidine-2,4-dione as a viscous milky oil. [M+1]=128.1. was added completion of reaction Upon cooling to room temperature

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

Procedure: To a cold (0° C.) solution of methylamine in ethanol (400 mL; 33% wt), ethyl acrylate (39.7 g, 0.397 mol) was added over a period of 20 minutes. The reaction mixture was stirred at 0° C. for 2 hours, and concentrated under vacuum. The crude product was used without further purification. The above crude product (21.8 g, 0.166 mol), diisopropylethylamine (28.9 mL, 0.166 mol), and 4-(N,N-dimethylamino)pyridine (2 g, 16 mmol) was dissolved in dichloromethane (300 mL) and cooled to 0° C. The mixture was treated with ethyl 3-chloro-3-oxopropionate (21.3 mL, 0.166 mol) and stirred at 0° C. for one hour. The mixture was allowed to warm up to room temperature and stirred overnight. The reaction mixture was partitioned with aq HCl (400 mL, 1M). The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound as yellow oil concentrated under vacuum The crude product was used without further purification cooled to 0° C stirred at 0° C. for one hour to warm up to room temperature stirred overnight The reaction mixture was partitioned with aq HCl (400 mL, 1M) The organic extract was washed with brine dried over anhydrous magnesium sulfate filtered concentrated under vacuum

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 50-mL round bottomed flask was added ethanol (4 mL) under argon, followed by sodium (0.121 g, 5.25 mmol). The mixture was stirred at room temperature for 15 min, during which a solution of ethyl 3-((3-ethoxy-3-oxopropyl)(methyl)amino)-3-oxopropanoate (1.17 g, 4.77 mmol) in ethanol (5 mL) was added. The resulting clear, colorless mixture was heated at 80° C. for 1 h, during which LC-MS indicated completion of reaction and a clean conversion to the desired ethyl 1-methyl-2,4-dioxopiperidine-3-carboxylate intermediate. Upon cooling to room temperature, the reaction was diluted with Et2O, resulting in the formation of a white precipitate (desired product). The white precipitate was collected via filtration, taken up in 5% aqueous HCl solution (8 mL), and refluxed for 1 h. The cooled mixture was extracted with CH2Cl2 (5×) and the combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% EtOAc/Hexanes to 100% EtOAc) afforded 1-methylpiperidine-2,4-dione as a viscous milky oil. [M+1]=128.1. was added completion of reaction Upon cooling to room temperature