哌嗪-2,5-二酮

反应条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 25.0 g of global 2,5-piperazinedione 1 [2,5-piperazinedione (Aldrich G640-6), 25.0 g, 0.218 mol] in 100 mL of acetic anhydride (Ac2O) was mixed with sodium acetate (NaOAc) (17.96 g, 0.0218 mol). The mixture was heated at 110° C. for 8 h using a double coiled condenser under an Ar atmosphere. After Ac2O was removed by evaporation, the residue was dissolved in AcOEt, washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4, and concentrated in vacuo. The residue was triturated with ether to form a solid. This solid was recrystallized from EtOAc with ether-hexane to afford 26.4 g (61%) of N,N′-diacetyl-2,5-piperazinedione 1. After Ac2O was removed by evaporation the residue was dissolved in AcOEt washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4 concentrated in vacuo The residue was triturated with ether to form a solid This solid was recrystallized from EtOAc with ether-hexane

反应条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 25.0 g of global 2,5-piperazinedione 1 [2,5-piperazinedione (Aldrich G640-6), 25.0 g, 0.218 mol] in 100 mL of acetic anhydride (Ac2O) was mixed with sodium acetate (NaOAc) (17.96 g, 0.0218 mol). The mixture was heated at 110° C. for 8 h using a double coiled condenser under an Ar atmosphere. After Ac2O was removed by evaporation, the residue was dissolved in AcOEt, washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4, and concentrated in vacuo. The residue was triturated with ether to form a solid. This solid was recrystallized from EtOAc with ether-hexane to afford 26.4 g (61%) of N,N′-diacetyl-2,5-piperazinedione 1. After Ac2O was removed by evaporation the residue was dissolved in AcOEt washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4 concentrated in vacuo The residue was triturated with ether to form a solid This solid was recrystallized from EtOAc with ether-hexane

反应条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 25.0 g of global 2,5-piperazinedione 1 [2,5-piperazinedione (Aldrich G640-6), 25.0 g, 0.218 mol] in 100 mL of acetic anhydride (Ac2O) was mixed with sodium acetate (NaOAc) (17.96 g, 0.0218 mol). The mixture was heated at 110° C. for 8 h using a double coiled condenser under an Ar atmosphere. After Ac2O was removed by evaporation, the residue was dissolved in AcOEt, washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4, and concentrated in vacuo. The residue was triturated with ether to form a solid. This solid was recrystallized from EtOAc with ether-hexane to afford 26.4 g (61%) of N,N′-diacetyl-2,5-piperazinedione 1. After Ac2O was removed by evaporation the residue was dissolved in AcOEt washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4 concentrated in vacuo The residue was triturated with ether to form a solid This solid was recrystallized from EtOAc with ether-hexane

反应条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 25.0 g of global 2,5-piperazinedione 1 [2,5-piperazinedione (Aldrich G640-6), 25.0 g, 0.218 mol] in 100 mL of acetic anhydride (Ac2O) was mixed with sodium acetate (NaOAc) (17.96 g, 0.0218 mol). The mixture was heated at 110° C. for 8 h using a double coiled condenser under an Ar atmosphere. After Ac2O was removed by evaporation, the residue was dissolved in AcOEt, washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4, and concentrated in vacuo. The residue was triturated with ether to form a solid. This solid was recrystallized from EtOAc with ether-hexane to afford 26.4 g (61%) of N,N′-diacetyl-2,5-piperazinedione 1. After Ac2O was removed by evaporation the residue was dissolved in AcOEt washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4 concentrated in vacuo The residue was triturated with ether to form a solid This solid was recrystallized from EtOAc with ether-hexane

反应条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 25.0 g of global 2,5-piperazinedione 1 [2,5-piperazinedione (Aldrich G640-6), 25.0 g, 0.218 mol) in 100 mL of acetic anhydride (Ac2O) was mixed with sodium acetate (NaOAc) (17.96 g, 0.0218 mol). The mixture was heated at 110° C. for 8 h using a double coiled condenser under an Ar atmosphere. After Ac2O was removed by evaporation, the residue was dissolved in AcOEt, washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4, and concentrated in vacuo. The residue was triturated with ether to form a solid. This solid was recrystallized from EtOAc with ether-hexane to afford 26.4 g (61%) of N,N′-diacetyl-2,5-piperazinedione 1. After Ac2O was removed by evaporation the residue was dissolved in AcOEt washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4 concentrated in vacuo The residue was triturated with ether to form a solid This solid was recrystallized from EtOAc with ether-hexane

反应条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 25.0 g of global 2,5-piperazinedione 1 [2,5-piperazinedione (Aldrich G640-6), 25.0 g, 0.218 mol] in 100 mL of acetic anhydride (Ac2O) was mixed with sodium acetate (NaOAc) (17.96 g, 0.0218 mol). The mixture was heated at 110° C. for 8 h using a double coiled condenser under an Ar atmosphere. After Ac2O was removed by evaporation, the residue was dissolved in AcOEt, washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4, and concentrated in vacuo. The residue was triturated with ether to form a solid. This solid was recrystallized from EtOAc with ether-hexane to afford 26.4 g (61%) of N,N′-diacetyl-2,5-piperazinedione 1. After Ac2O was removed by evaporation the residue was dissolved in AcOEt washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4 concentrated in vacuo The residue was triturated with ether to form a solid This solid was recrystallized from EtOAc with ether-hexane

反应条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 25.0 g of global 2,5-piperazinedione 1 [2,5-piperazinedione (Aldrich G640-6), 25.0 g, 0.218 mol] in 100 mL of acetic anhydride (Ac2O) was mixed with sodium acetate (NaOAc) (17.96 g, 0.0218 mol). The mixture was heated at 110° C. for 8 h using a double coiled condenser under an Ar atmosphere. After Ac2O was removed by evaporation, the residue was dissolved in AcOEt, washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4, and concentrated in vacuo. The residue was triturated with ether to form a solid. This solid was recrystallized from EtOAc with ether-hexane to afford 26.4 g (61%) of N,N′-diacetyl-2,5-piperazinedione 1. After Ac2O was removed by evaporation the residue was dissolved in AcOEt washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4 concentrated in vacuo The residue was triturated with ether to form a solid This solid was recrystallized from EtOAc with ether-hexane

反应条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 25.0 g of global 2,5-piperazinedione 1 [2,5-piperazinedione (Aldrich G640-6), 25.0 g, 0.218 mol] in 100 mL of acetic anhydride (Ac2O) was mixed with sodium acetate (NaOAc) (17.96 g, 0.0218 mol). The mixture was heated at 110° C. for 8 h using a double coiled condenser under an Ar atmosphere. After Ac2O was removed by evaporation, the residue was dissolved in AcOEt, washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4, and concentrated in vacuo. The residue was triturated with ether to form a solid. This solid was recrystallized from EtOAc with ether-hexane to afford 26.4 g (61%) of N,N′-diacetyl-2,5-piperazinedione 1. After Ac2O was removed by evaporation the residue was dissolved in AcOEt washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4 concentrated in vacuo The residue was triturated with ether to form a solid This solid was recrystallized from EtOAc with ether-hexane

反应条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 25.0 g of global 2,5-piperazinedione 1 [2,5-piperazinedione (Aldrich G640-6), 25.0 g, 0.218 mol] in 100 mL of acetic anhydride (Ac2O) was mixed with sodium acetate (NaOAc) (17.96 g, 0.0218 mol). The mixture was heated at 110° C. for 8 h using a double coiled condenser under an Ar atmosphere. After Ac2O was removed by evaporation, the residue was dissolved in AcOEt, washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4, and concentrated in vacuo. The residue was triturated with ether to form a solid. This solid was recrystallized from EtOAc with ether-hexane to afford 26.4 g (61%) of N,N′-diacetyl-2,5-piperazinedione 1. After Ac2O was removed by evaporation the residue was dissolved in AcOEt washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4 concentrated in vacuo The residue was triturated with ether to form a solid This solid was recrystallized from EtOAc with ether-hexane

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (360 mg, 1 mmol), piperazine-2,5-dione (570 mg, 5 mmol), copper(I) iodide (115 mg, 0.6 mmol), N,N-dimethylglycine hydrochloride (112 g, 0.8 mmol) and potassium carbonate (415 mg, 3 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 12 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% formic acid in water) afforded 2-[3-(2,5-dioxo-piperazin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (46 mg, 11%) as a grey solid: LC/MS m/e calcd for C22H23N3O4 (M+H)+: 394.45, observed: 394.1. 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% formic acid in water)

反应条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 25.0 g of global 2,5-piperazinedione 1 [2,5-piperazinedione (Aldrich G640-6), 25.0 g, 0.218 mol] in 100 mL of acetic anhydride (Ac2O) was mixed with sodium acetate (NaOAc) (17.96 g, 0.0218 mol). The mixture was heated at 110° C. for 8 h using a double coiled condenser under an Ar atmosphere. After Ac2O was removed by evaporation, the residue was dissolved in AcOEt, washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4, and concentrated in vacuo. The residue was triturated with ether to form a solid. This solid was recrystallized from EtOAc with ether-hexane to afford 26.4 g (61%) of N,N′-diacetyl-2,5-piperazinedione 1. After Ac2O was removed by evaporation the residue was dissolved in AcOEt washed with 10% citric acid, 10% NaHCO3 and saturated NaCl (three times each), dried over Na2SO4 concentrated in vacuo The residue was triturated with ether to form a solid This solid was recrystallized from EtOAc with ether-hexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The sequence of reactions in Reaction Scheme 9a is comparable to those set forth in Reaction Scheme 9 except that N-acetylglycine XVIII is deacylated to form 2,5-diketopiperazine XXX. 2,5-diketopiperazine XXX is then reacted with formaldehyde and H3PO3, PCl3 or other H3PO3 source to produce N-(phosphonomethyl)glycine I and acetic acid. Acetic acid which is produced in the hydrolysis step can be reacted with ammonia to generate acetamide for the carboxymethylation step.