利奈唑胺杂质41

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Bis(phenylmethyl) 1,2-hydrazinedicarboxylate (5.91 g, 19.68 mmol) was placed in a 500 ml round bottomed flask and acetonitrile (150 ml) was added followed by cesium carbonate (14.11 g, 43.3 mmol). 1,1-Dimethylethyl 2,4-dibromobutanoate (4.00 ml, 19.68 mmol) was added dropwise and the reaction was heated to 60° C. and stirred overnight. The resulting solution was cooled to room temperature and passed through a pad of celite. The filtrate was concentrated and purified via combiflash silica gel chromatography (0-100% EtOAC in hex) yielding 3-(1,1-dimethylethyl) 1,2-bis(phenylmethyl) 1,2,3-pyrazolidinetricarboxylate (5.3 g, 12.03 mmol, 61.1% yield) as a pale yellow oil. The resulting solution was cooled to room temperature The filtrate was concentrated purified via combiflash silica gel chromatography (0-100% EtOAC in hex)

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

实验步骤: Benzyl chloroformate (19.73 mL, 140 mmol) was added dropwise to a solution of hydrazine (2 mL, 63.7 mmol) in methanol (200 mL). Approximately half way through the addition, dropwise addition of a solution of sodium carbonate (14.86 g, 140 mmol) in water (150 mL) commenced. The resulting slurry was stirred for about 45 min before being filtered under suction, isolating a solid which was washed with ice water. The resulting filtrate was concentrated to remove the methanol, yielding a small quantity of solid material upon filtration. This solid material was again washed with ice water. The combined solids were recrystallized from straight toluene. The resulting white solid was dried in a vacuum oven at 60° C. for 5 hours. This yielded bis(phenylmethyl) 1,2-hydrazinedicarboxylate (13.74 g, 45.8 mmol, 71.8% yield) as a white crystalline solid. before being filtered under suction isolating a solid which was washed with ice water The resulting filtrate was concentrated to remove the methanol yielding a small quantity of solid material upon filtration This solid material was again washed with ice water The combined solids were recrystallized from straight toluene The resulting white solid was dried in a vacuum oven at 60° C. for 5 hours

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of bis(benzyloxycarbonyl)hydrazine (2.65 g, 8.83 mol) in acetonitrile (30 L) was charged into 100 L-reactor. Cesium carbonate (6.00 kg, 18.4 mol) and tert-butyl 2,4-dibromobutyrate (2.65 kg, 8.83 mol) were added into the above solution. The mixture solution was heated at 50° C. for 2.5 h until the two starting materials were completely consumed. The mixture solution was cooled to room temperature. A filtration was performed to remove some undissolved materials. The filtrate was concentrated under vacuum to afford product (4000 g crude product) as a brown oil. were completely consumed The mixture solution was cooled to room temperature A filtration to remove some undissolved materials The filtrate was concentrated under vacuum

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of sodium hydroxide (2.50 kg, 62.5 mol) in water (40 L) was charged into an 100 L reactor. Hydrazine hydrate (2.00 kg, 40 mol) and THF (8 L) were added into the above solution. The mixture solution was cooled at 0° C. A pre-prepared solution of Cbz-Cl (13.60 kg CbzCl, 61.99 mol) in 2 L THF was added dropwise to the solution while maintaining the temperature at 0° C. The reaction was allowed to stir for an additional 4 h and a solid precipitated from the solution. The solid was collected by filtration, which was suspended in toluene (5 L). The suspended solution was heated at 80° C., which became clear. The water in the crude product was removed completely under reflux using a Dean-Stark apparatus. The resulting solution was cooled to room temperature and the product precipitated. The product was obtained after filtration to afford bis(phenylmethyl) 1,2-hydrazinedicarboxylate (7.8 Kg, 26 mol, 65%) as a white solid. while maintaining the temperature at 0° C a solid precipitated from the solution The solid was collected by filtration, which The suspended solution was heated at 80° C. The water in the crude product was removed completely under reflux The resulting solution was cooled to room temperature the product precipitated The product was obtained after filtration