tert-butyl N-(2-hydrazinyl-2-oxoethyl)carbamate

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

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

Procedure: To a stirred solution of methyl (tert-butyloxycarbonyl)glycinate (8.54 g, 45.1 mmol) was added hydrazine hydrate (4.4 mL, 90.5 mmol) and the reaction was heated under reflux for 16 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane (100 mL) and water (100 mL). The phases were separated, the aqueous phase evaporated in vacuo to low volume and extracted with 5% methanol/dichloromethane (2×100 mL) The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to give the product as a white crystalline solid, 5.27 g (62%). the reaction was heated under reflux for 16 hours The solvent was removed in vacuo the residue partitioned between dichloromethane (100 mL) and water (100 mL) The phases were separated the aqueous phase evaporated in vacuo to low volume extracted with 5% methanol/dichloromethane (2×100 mL) The organic extracts dried over magnesium sulfate concentrated in vacuo

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

Procedure: To a stirred solution of methyl (tert-butyloxycarbonyl)glycinate (8.54 g, 45.1 mmol) was added hydrazine hydrate (4.4 mL, 90.5 mmol) and the reaction was heated under reflux for 16 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane (100 mL) and water (100 mL). The phases were separated, the aqueous phase evaporated in vacuo to low volume and extracted with 5% methanol/dichloromethane (2×100 mL) The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to give the product as a white crystalline solid, 5.27 g (62%). the reaction was heated under reflux for 16 hours The solvent was removed in vacuo the residue partitioned between dichloromethane (100 mL) and water (100 mL) The phases were separated the aqueous phase evaporated in vacuo to low volume extracted with 5% methanol/dichloromethane (2×100 mL) The organic extracts dried over magnesium sulfate concentrated in vacuo

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

Procedure: HATU (4.9 g, 12.9 mmol) and tert-butyl 2-hydrazinyl-2-oxoethylcarbamate (2.2 g, 11.4 mmol) were added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (3 g, 10.8 mmol) in CH2Cl2 (50 mL) at 0° C. DIPEA (4.2 g, 32.6 mmol) was then added and the reaction mixture was stirred at 0° C. for 12 hrs. The reaction mixture was then washed with water, and saturated sodium chloride, dried over Na2SO4, and concentrated. The crude sample was purified by silica gel column chromatography (1 to 10% MeOH/DCM) to give tert-butyl (2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)carbamate (3.5 g, 62%) as a white solid. ESI-MS (EI+, m/z): 448.2 [M+H]+. The reaction mixture was then washed with water, and saturated sodium chloride dried over Na2SO4 concentrated The crude sample was purified by silica gel column chromatography (1 to 10% MeOH/DCM)

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

Procedure: To a solution of (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (153 mg, 0.554 mmol) in tetrahydrofuran (3 mL) were added triethylamine (0.232 mL) and isobutyl chloroformate (89.1 μl) under ice-cooling, followed by agitating at 0° C. for 45 minutes. To the reaction solution was added a solution of tert-butyl 2-hydrazinyl-2-oxoethylcarbamate (129 mg, prepared following a procedure analogous to Reference Example 5 and Reference Example 6) in tetrahydrofuran (3 mL) at 0° C., followed by stirring at room temperature for 2.5 hours and concentrating under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3-0/10) to afford 179 mg of the title compound (yield 72%). cooling prepared at 0° C. by stirring at room temperature for 2.5 hours concentrating under reduced pressure The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3-0/10)

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

Procedure: To a solution of (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (153 mg, 0.554 mmol) in tetrahydrofuran (3 mL) were added triethylamine (0.232 mL) and isobutyl chloroformate (89.1 μl) under ice-cooling, followed by agitating at 0° C. for 45 minutes. To the reaction solution was added a solution of tert-butyl 2-hydrazinyl-2-oxoethylcarbamate (129 mg, prepared following a procedure analogous to Reference Example 5 and Reference Example 6) in tetrahydrofuran (3 mL) at 0° C., followed by stirring at room temperature for 2.5 hours and concentrating under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3-0/10) to afford 179 mg of the title compound (yield 72%). cooling prepared at 0° C. by stirring at room temperature for 2.5 hours concentrating under reduced pressure The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3-0/10)

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

Procedure: HATU (4.9 g, 12.9 mmol) and tert-butyl 2-hydrazinyl-2-oxoethylcarbamate (2.2 g, 11.4 mmol) were added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (3 g, 10.8 mmol) in CH2Cl2 (50 mL) at 0° C. DIPEA (4.2 g, 32.6 mmol) was then added and the reaction mixture was stirred at 0° C. for 12 hrs. The reaction mixture was then washed with water, and saturated sodium chloride, dried over Na2SO4, and concentrated. The crude sample was purified by silica gel column chromatography (1 to 10% MeOH/DCM) to give tert-butyl (2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)carbamate (3.5 g, 62%) as a white solid. ESI-MS (EI+, m/z): 448.2 [M+H]+. The reaction mixture was then washed with water, and saturated sodium chloride dried over Na2SO4 concentrated The crude sample was purified by silica gel column chromatography (1 to 10% MeOH/DCM)

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

Procedure: HATU (4.9 g, 12.9 mmol) and tert-butyl 2-hydrazinyl-2-oxoethylcarbamate (2.2 g, 11.4 mmol) were added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (3 g, 10.8 mmol) in CH2Cl2 (50 mL) at 0° C. DIPEA (4.2 g, 32.6 mmol) was then added and the reaction mixture was stirred at 0° C. for 12 hrs. The reaction mixture was then washed with water, and saturated sodium chloride, dried over Na2SO4, and concentrated. The crude sample was purified by silica gel column chromatography (1 to 10% MeOH/DCM) to give tert-butyl (2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)carbamate (3.5 g, 62%) as a white solid. ESI-MS (EI+, m/z): 448.2 [M+H]+. The reaction mixture was then washed with water, and saturated sodium chloride dried over Na2SO4 concentrated The crude sample was purified by silica gel column chromatography (1 to 10% MeOH/DCM)

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

Procedure: To a stirred solution of methyl (tert-butyloxycarbonyl)glycinate (8.54 g, 45.1 mmol) was added hydrazine hydrate (4.4 mL, 90.5 mmol) and the reaction was heated under reflux for 16 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane (100 mL) and water (100 mL). The phases were separated, the aqueous phase evaporated in vacuo to low volume and extracted with 5% methanol/dichloromethane (2×100 mL) The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to give the product as a white crystalline solid, 5.27 g (62%). the reaction was heated under reflux for 16 hours The solvent was removed in vacuo the residue partitioned between dichloromethane (100 mL) and water (100 mL) The phases were separated the aqueous phase evaporated in vacuo to low volume extracted with 5% methanol/dichloromethane (2×100 mL) The organic extracts dried over magnesium sulfate concentrated in vacuo

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

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

Procedure: Under a nitrogen atmosphere in a round bottom flask, 5-ethyl-6-methoxy-2-methyl-nicotinic acid (500 mg, 2.56 mmol) of Step 2, Example 14 is dissolved in dichloromethane (60 mL). O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (838 mg, 2.82 mmol) is added, followed by hydroxybenzotriazole hydrate (392 mg, 2.56 mmol). The resulting mixture is stirred at rt for 30 min to give a suspension, which is treated with hydrazinocarbonylmethyl-carbamic acid tert-butyl ester (509 mg, 2.69 mmol) followed by N-ethyl-diisopropylamine (1.16 mL, 6.66 mmol). The resulting solution is stirred at rt for 135 hr, LC/MS shows the reaction to be complete. The reaction is diluted with water and the mixture is extracted with five portions of dichloromethane, the combined extract is washed with saturated aqueous sodium bicarbonate (30 mL), then dried over magnesium sulfate, filtered and evaporated. The crude product is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1). Fractions containing the product are combined and evaporated and repurified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1 increasing to 1:1) to obtain {2-[N′-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hydrazino]-2-oxo-ethyl}-carbamic acid tert-butyl ester (686 mg, 73% yield) as a white solid. MS: m/e 755 (100%) (2M+Na), 367 (70%) (M+H); 1H NMR (300 MHz, CDCl3, δ, ppm): 8.97 (1H, br.s), 8.22 (1H, br.s), 7.44 (1H, s), 5.21 (1H, br.t), 3.96 (5H, m), 2.59 (3H, s), 2.53 (2H, q), 1.48 (9H, s), 1.18 (3H, t). to give a suspension, which The resulting solution is stirred at rt for 135 hr the reaction the mixture is extracted with five portions of dichloromethane the combined extract is washed with saturated aqueous sodium bicarbonate (30 mL) dried over magnesium sulfate filtered evaporated The crude product is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1) Fractions containing the product evaporated repurified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1 increasing to 1:1)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared essentially in accordance with the procedures of Tetrahedron Letters, Vol 36, No. 37 P6591-6594 as set forth herein. Under a nitrogen atmosphere in a round bottom flask, tert-butoxycarbonylamino-acetic acid methyl ester (2.0 mL, 13.5 mmol) is dissolved in absolute ethanol (50 mL) and anhydrous hydrazine (0.45 mL, 14.3 mmol) is added. The resulting mixture is heated in an oil bath at 60° C. for 3 hours then 80° C. for 5.5 hours. The reaction mixture is evaporated and the residue partitioned between water (50 mL) and dichloromethane (50 mL). The aqueous layer is extracted with dichloromethane (2×10 mL). The combined dichloromethane extracts are washed with water (2×30 mL). The dichloromethane layer is dried over magnesium sulfate and evaporated to give a solid that is triturated with diethyl ether to give hydrazinocarbonylmethyl-carbamic acid tert-butyl ester (1.94 g, 76% yield). The title compound was prepared essentially in accordance with the procedures of Tetrahedron Letters, Vol 36 The reaction mixture is evaporated the residue partitioned between water (50 mL) and dichloromethane (50 mL) The aqueous layer is extracted with dichloromethane (2×10 mL) The combined dichloromethane extracts are washed with water (2×30 mL) The dichloromethane layer is dried over magnesium sulfate evaporated to give a solid that is triturated with diethyl ether