1-methylpiperazine-2,3-dione

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

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.34 g of 60% sodium hydride was added to a solution of 1.00 g of 1-methyl-2,3-piperazinedione in 10 mL of N,N-dimethylformamide, and this mixture was stirred for 10 minutes at 50° C. Then, 0.88 mL of 4-fluorobenzaldehyde was added thereto and the mixture was stirred for 30 minutes at 120° C. The mixture was cooled to room temperature, and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=15:1] to yield 0.80 g of 4-(4-methyl-2,3-dioxo-1-piperazinyl)benzaldehyde as white solid. the mixture was stirred for 30 minutes at 120° C The mixture was cooled to room temperature the solvent was distilled out thereof under reduced pressure The resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=15:1]

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.34 g of 60% sodium hydride was added to a solution of 1.00 g of 1-methyl-2,3-piperazinedione in 10 mL of N,N-dimethylformamide, and this mixture was stirred for 10 minutes at 50° C. Then, 0.88 mL of 4-fluorobenzaldehyde was added thereto and the mixture was stirred for 30 minutes at 120° C. The mixture was cooled to room temperature, and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=15:1] to yield 0.80 g of 4-(4-methyl-2,3-dioxo-1-piperazinyl)benzaldehyde as white solid. the mixture was stirred for 30 minutes at 120° C The mixture was cooled to room temperature the solvent was distilled out thereof under reduced pressure The resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=15:1]

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (500 mg, 1.4 mmol), 1-methyl-piperazine-2,3-dione (267 mg, 2.1 mmol), copper(I) iodide (80 mg, 0.4 mmol), N,N-dimethylglycine hydrochloride (117 mg, 0.8 mmol) and potassium carbonate (769 mg, 5.6 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3,3-dimethyl-2-[3-(4-methyl-2,3-dioxo-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (456 mg, 80%) as a white solid: LC/MS m/e calcd for C23H25N3O4 (M+H)+: 408.47, observed: 408.1. Then the reaction mixture cooled to room temperature The reaction mixture was extracted with ethyl acetate (2×150 mL) washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL) dried over anhydrous sodium sulfate concentrated in vacuo Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (500 mg, 1.4 mmol), 1-methyl-piperazine-2,3-dione (267 mg, 2.1 mmol), copper(I) iodide (80 mg, 0.4 mmol), N,N-dimethylglycine hydrochloride (117 mg, 0.8 mmol) and potassium carbonate (769 mg, 5.6 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3,3-dimethyl-2-[3-(4-methyl-2,3-dioxo-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (456 mg, 80%) as a white solid: LC/MS m/e calcd for C23H25N3O4 (M+H)+: 408.47, observed: 408.1. Then the reaction mixture cooled to room temperature The reaction mixture was extracted with ethyl acetate (2×150 mL) washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL) dried over anhydrous sodium sulfate concentrated in vacuo Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.34 g of 60% sodium hydride was added to a solution of 1.00 g of 1-methyl-2,3-piperazinedione in 10 mL of N,N-dimethylformamide, and this mixture was stirred for 10 minutes at 50° C. Then, 0.88 mL of 4-fluorobenzaldehyde was added thereto and the mixture was stirred for 30 minutes at 120° C. The mixture was cooled to room temperature, and the solvent was distilled out thereof under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=15:1] to yield 0.80 g of 4-(4-methyl-2,3-dioxo-1-piperazinyl)benzaldehyde as white solid. the mixture was stirred for 30 minutes at 120° C The mixture was cooled to room temperature the solvent was distilled out thereof under reduced pressure The resultant residue was purified by silica gel column chromatography [eluent; chloroform:ethanol=15:1]