泰地唑胺杂质49

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: To a 12-L, three-neck, round-bottom flask equipped with an overhead stirrer, nitrogen inlet/outlet, addition funnel and thermocouple was charged 4-bromo-3-fluoroaniline (800.0 g, 4.21 mol, Matrix lot #Q13H), THF (6.4 L, 8 vol), and solid sodium bicarbonate (530.5 g, 6.32 mol, 1.5 eq). The addition funnel was charged with benzyl chloroformate (861.9 g, 5.05 mol, 1.2 eq), which was added dropwise to the reactor over 70 minutes. The temperature of the reaction was maintained below 20° C. with an ice water bath. The batch was aged 1 hour at room temperature at which point HPLC analysis indicated that the reaction was complete. The reaction mixture was transferred to a 22-L flask and the mixture was diluted with water (6.4 L, 8 vol). The two-phase mixture was warmed to 50° C. and held at temperature for 16 hours to quench the excess benzyl chloroformate. The mixture was transferred hot to a separatory funnel to remove the lower aqueous phase. A rag layer was observed which was taken with the aqueous layer. The THF layer was filtered through Whatman #1 filter paper to remove some particulates, and the mixture was transferred back to a 22-L flask equipped for distillation. Heptane was added in portions and distilled to remove the THF. (Note that it is best to distill some of the THF out first before adding the first amount of heptane.) A total of 26.5 L of heptane was added, and the total distillate collected was 25 L. At this point, the pot temperature had reached 97.7° C. and the distillate coming over contained 0.9% THF by 1H NMR analysis. The mixture was cooled to room temperature and the thick white slurry was filtered. The filter cake was washed with heptane (4 L). The product was dried in a vacuum oven at 40° C. to give 1257.0 g of intermediate 5 (92% yield). The HPLC assay was 98.3% (AUC). was added dropwise to the reactor over 70 minutes The temperature of the reaction was maintained below 20° C. with an ice water bath The reaction mixture was transferred to a 22-L flask held at temperature for 16 hours to quench the excess benzyl chloroformate The mixture was transferred hot to a separatory funnel to remove the lower aqueous phase The THF layer was filtered through Whatman #1 filter paper to remove some particulates the mixture was transferred back to a 22-L flask equipped for distillation Heptane was added in portions distilled to remove the THF to distill some of the THF out first before adding the first amount of heptane ) A total of 26.5 L of heptane was added the total distillate collected had reached 97.7° C. The mixture was cooled to room temperature the thick white slurry was filtered The filter cake was washed with heptane (4 L) The product was dried in a vacuum oven at 40° C.

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Butyl lithium (2.3M in n-hexanes, 118.3 ml, 0.272 mol, 1.06 eq) was added at −30° C. to anhydrous tert-butanol (25.0 g, 0.53 mol, 2.07 eq) in anhydrous THF (170 ml), under nitrogen. The mixture was stirred for 30 min at −30° C., and was then allowed to warm slowly to 0° C. After 30 min at 0° C., the (4-bromo-3-fluoro-phenyl)-carbamic acid benzyl ester (83 g, 0.256 mol, 1 eq) was added portionwise, keeping the temperature cold, and the mixture was stirred for an additional 30 min at 0° C. To this ice cold mixture, R(−)-glycidyl butyrate (39.7 ml, 0.288 mol, 1.12 eq) were added and the mixture allowed to come gradually to room temperature. The mixture was extracted with saturated sodium chloride solution and the organic phase was dried over MgSO4, filtrated and evaporated. The product was obtained after recrystallisation of the crude product with ethyl acetate, to give (64.1 g, 86.4%). to warm slowly to 0° C After 30 min at 0° C. the mixture was stirred for an additional 30 min at 0° C to come gradually to room temperature The mixture was extracted with saturated sodium chloride solution the organic phase was dried over MgSO4 filtrated evaporated The product was obtained after recrystallisation of the crude product with ethyl acetate to give (64.1 g, 86.4%)

反应条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium hydrogen carbonate (27.63 g, 0.329 mol, 1.25 eq) and a saturated solution of sodium hydrogen carbonate (333 ml) were added to a stirred solution of 4-bromo-3-fluoroaniline (50.0 g, 0.263 mol, 1 eq) in acetone (660 ml). The resulting mixture was cooled to 15° C. and benzyl chloroformate (39 ml, 0.276 mol, 1.05 eq) was added gradually, taking care that the reaction temperature did not exceed 22° C. The mixture was stirred over 90 mins at room temperature and the acetone was removed under vacuum. The aqueous layer was then extracted with ethyl acetate (3×150 ml). The combined organic layers were then washed with a saturated sodium chloride solution, and dried over MgSO4. After filtration, the solvent was removed, and n-hexane added. The mixture was stirred during 30 min at room temperature, the crystals were filtrated and washed with hexane to give the first crop of solid. The filtrate was evaporated, and the solid mixed with heptane at 0° C. and stirred during 30 min. The product was again filtered, to give the second crop of solid. The two crops were then combined, to give the product (85.3 g, quantitative) as of solid. did not exceed 22° C the acetone was removed under vacuum The aqueous layer was then extracted with ethyl acetate (3×150 ml) The combined organic layers were then washed with a saturated sodium chloride solution dried over MgSO4 After filtration the solvent was removed n-hexane added The mixture was stirred during 30 min at room temperature the crystals were filtrated washed with hexane to give the first crop of solid The filtrate was evaporated the solid mixed with heptane at 0° C. stirred during 30 min The product was again filtered to give the second crop of solid to give the product (85.3 g, quantitative) as of solid

反应条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Butyl lithium (2.3M in n-hexanes, 118.3 ml, 0.272 mol, 1.06 eq) was added at −30° C. to anhydrous tert-butanol (25.0 g, 0.53 mol, 2.07 eq) in anhydrous THF (170 ml), under nitrogen. The mixture was stirred for 30 min at −30° C., and was then allowed to warm slowly to 0° C. After 30 min at 0° C., the (4-bromo-3-fluoro-phenyl)-carbamic acid benzyl ester (83 g, 0.256 mol, 1 eq) was added portionwise, keeping the temperature cold, and the mixture was stirred for an additional 30 min at 0° C. To this ice cold mixture, R(−)-glycidyl butyrate (39.7 ml, 0.288 mol, 1.12 eq) were added and the mixture allowed to come gradually to room temperature. The mixture was extracted with saturated sodium chloride solution and the organic phase was dried over MgSO4, filtrated and evaporated. The product was obtained after recrystallisation of the crude product with ethyl acetate, to give (64.1 g, 86.4%). to warm slowly to 0° C After 30 min at 0° C. the mixture was stirred for an additional 30 min at 0° C to come gradually to room temperature The mixture was extracted with saturated sodium chloride solution the organic phase was dried over MgSO4 filtrated evaporated The product was obtained after recrystallisation of the crude product with ethyl acetate to give (64.1 g, 86.4%)

反应条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Sodium hydrogen carbonate (27.63 g, 0.329 mol, 1.25 eq) and a saturated solution of sodium hydrogen carbonate (333 ml) were added to a stirred solution of 4-bromo-3-fluoroaniline (50.0 g, 0.263 mol, 1 eq) in acetone (660 ml). The resulting mixture was cooled to 15° C. and benzyl chloroformate (39 ml, 0.276 mol, 1.05 eq) was added gradually, taking care that the reaction temperature did not exceed 22° C. The mixture was stirred over 90 mins at room temperature and the acetone was removed under vacuum. The aqueous layer was then extracted with ethyl acetate (3×150 ml). The combined organic layers were then washed with a saturated sodium chloride solution, and dried over MgSO4. After filtration, the solvent was removed, and n-hexane added. The mixture was stirred during 30 min at room temperature, the crystals were filtrated and washed with hexane to give the first crop of solid. The filtrate was evaporated, and the solid mixed with heptane at 0° C. and stirred during 30 min. The product was again filtered, to give the second crop of solid. The two crops were then combined, to give the product (85.3 g, quantitative) as of solid. did not exceed 22° C the acetone was removed under vacuum The aqueous layer was then extracted with ethyl acetate (3×150 ml) The combined organic layers were then washed with a saturated sodium chloride solution dried over MgSO4 After filtration the solvent was removed n-hexane added The mixture was stirred during 30 min at room temperature the crystals were filtrated washed with hexane to give the first crop of solid The filtrate was evaporated the solid mixed with heptane at 0° C. stirred during 30 min The product was again filtered to give the second crop of solid to give the product (85.3 g, quantitative) as of solid

反应条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 9.72 g (4-bromo-3-fluoro-phenyl)-carbamic acid benzyl ester (30 mmol), 6 g ethyl acrylate (60 mmol), 10.2 ml DIPEA (60 mmol), 112 mg palladium acetate (, 3 mmol), and 1.57 g triphenylphosphine (6 mmol) in 10 ml DMF were stirred at 130° C. for 48 h. The reaction was monitored by TLC. The DMF was evaporated, the residue dissolved in dichloromethane, washed with water and brine, dried over Mg sulfate, filtered and the filtrate evaporated. The residue was purified by chromatography, using a 7/3 N-hexane/ethyl acetate mixture as eluent. The DMF was evaporated the residue dissolved in dichloromethane washed with water and brine dried over Mg sulfate filtered the filtrate evaporated The residue was purified by chromatography

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

实验步骤: To a solution of 10 g of 4-bromo-3-fluoroaniline (52 mmol) in 300 ml acetone were added successively 150 ml of a saturated sodium bicarbonate solution and at 0° C. 9 ml of benzyl chloroformate (63 mmol). The reaction was monitored by TLC. The acetone was evaporated, the residue extracted twice with ethyl acetate, washed with water and brine, dried and evaporated. The residue was crystallized from an ethyl acetate/hexane mixture. at 0° C The acetone was evaporated the residue extracted twice with ethyl acetate washed with water and brine dried evaporated The residue was crystallized from an ethyl acetate/hexane mixture