tert-butyl 2-oxo-3,5-dihydro-1H-1,4-benzodiazepine-4-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (10.0 g, 38.16 mmol) in dry THF (300 mL) at 0° C., was added potassium tert-butoxide (6.4 g, 56.76 mmol) under nitrogen atmosphere and the reaction mixture was stirred at this temperature for 30 min followed by dropwise addition of diethylchlorophosphate (11 mL, 76.3.3 mmol). The reaction mixture was stirred at 0° C. for 40 min. This solution was transferred via cannula to a suspension of potassium tert-butoxide (12.86 g, 114.56 mmol) and ethyl isocyanoacetate (11.66 mL, 102.65 mmol) in dry THF (150 mL), kept in a separate flask at 0° C. under nitrogen atmosphere. When the addition was complete, the reaction mixture was allowed to come to r.t. and stirred for 45 min. during which the reaction was complete as confirmed by TLC. Reaction mixture was cooled to 0° C. and quenched with 10% acetic acid solution and stirred for 20 min. The crude compound was extracted with ethylacetate. The organic layer was washed with water, separated, dried over Na2SO4 and concentrated in vacuo to afford the crude compound which was purified by column chromatography (neutral alumina using neutral alumina, 3:7 EtOAc:Pet.Ether) to afford a viscous gel which was further purified by crystallisation from diethyl ether and hexane to afford 4H,6H-2,5,10b-triaza-benzo[e]azulene-3,5-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester a white solid (4.4 g, 33%) The reaction mixture was stirred at 0° C. for 40 min kept in a separate flask at 0° C. under nitrogen atmosphere When the addition to come to r.t. stirred for 45 min. during which the reaction Reaction mixture quenched with 10% acetic acid solution stirred for 20 min The crude compound was extracted with ethylacetate The organic layer was washed with water separated dried over Na2SO4 concentrated in vacuo to afford the crude compound which was purified by column chromatography (neutral alumina using neutral alumina, 3:7 EtOAc:Pet.Ether) to afford a viscous gel which was further purified by crystallisation from diethyl ether and hexane

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium hydride (152.6 mg, 3.81 mmol, 60% suspension in mineral oil) was washed with hexane (2×2 mL) in a flame dried round bottomed flask under nitrogen atmosphere. To the resulting free floating powder, was added a solution of 2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (500 mg, 1.90 mmol) in dry DMF (10 mL) at 0° C. The reaction mixture was stirred at this temperature for 1 h. Ethyl bromoacetate (0.21 mL, 1.9 mmol) was added at 0° C. and the reaction mixture was allowed to come to r.t. and stirred overnight. After the completion of the reaction as confirmed by TLC, reaction mixture was cooled to 0° C. and saturated solution of ammonium chloride (3 mL) was added dropwise to the reaction mixture. The crude product was extracted with ethylacetate (3×10 mL). The combined organic layers were dried over Na2SO4 and solvents were removed in vacuo to afford 1-ethoxycarbonylmethyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (480 mg, 72%) as a viscous oil which was used as such without any further purification for the next step. dried round bottomed flask under nitrogen atmosphere to come to r.t. stirred overnight After the completion of the reaction as confirmed by TLC, reaction mixture The crude product was extracted with ethylacetate (3×10 mL) The combined organic layers were dried over Na2SO4 and solvents were removed in vacuo

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium hydride (18 mg, 0.45 mmol, 60% suspension in mineral oil) was washed with hexane (2×2 mL) in, a flame dried round bottomed flask under nitrogen atmosphere. To the resulting free floating powder, was added a solution of 2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (80 mg, 0.30 mmol) in dry DMF (3 mL) at 0° C. The reaction mixture was stirred at this temperature for 1 h. Iodomethane (0.0.19 mL, 0.30 mmol) was added at 0° C. and the reaction mixture was allowed to come to r.t. and stirred overnight. After the completion of the reaction as confirmed by TLC, reaction mixture was cooled to 0° C. and saturated solution of ammonium chloride (2 mL) was added dropwise to the reaction mixture. The crude product was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over Na2SO4 and the solvents were removed in vacuo to afford 1-methyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (75 mg, 89%) as a viscous oil which was used as such without any further purification for the next step. dried round bottomed flask under nitrogen atmosphere to come to r.t. stirred overnight After the completion of the reaction as confirmed by TLC, reaction mixture The crude product was extracted with ethyl acetate (2×10 mL) The combined organic layers were dried over Na2SO4 the solvents were removed in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (300 mg, 1.14 mmol) in dry DCM (10 mL) was added trifluoroacetic acid (3.42 mL, 3 mL/mmol. The reaction mixture was stirred at r.t. for 2 h. After completion of the reaction as confirmed by TLC, excess of trifluoroacetic acid and DCM were removed under vacuo to afford trifluoroacetic acid salt of 1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (295 mg, 93%) as a gummy solid. The crude compound was used as such without further purification for the next step. After completion of the reaction were removed under vacuo

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of [(2-amino-benzyl)-tert-butoxycarbonyl-amino]acetic acid methyl ester (640 mg, 2.18 mmol) in toluene (30 mL), was added HOBT (177 mg, 1.31 mmol). The reaction mixture was heated at 100° C. for 24 h. After the completion of reaction, as confirmed by TLC, the solvent was removed in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 7:13 EtOAc:Pet. Ether) to afford pure 2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester: (350 mg, 61%) as a solid. After the completion of reaction the solvent was removed in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 7:13 EtOAc:Pet. Ether)