反应详情

To a solution of 3-chloro-2-fluorophenol (180 mg, 1.20 mmol) in dry CH2Cl2 (10 mL), cooled to at 0° C., was added triphosgene (120 mg, 0.4 mmol) followed by dropwise addition of a solution of DIPEA (210 μL, 1.20 mmol) in CH2Cl2 (5 mL). The mixture was allowed to warm to RT and stirring was continued for 1 h. The reaction mixture was then added dropwise to a solution of (1R,3S,5R)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (170 mg, 0.80 mmol) (prepared as described in Part B) and DIPEA (168 μL, 0.96 mmol) in CH2Cl2 (10 mL) at RT. After stirring for 2 h, the reaction was quenched by addition of methanol (2 mL) and water with vigorous stirring. The mixture was extracted with CH2Cl2 (2×), the combined organics were washed with brine, dried (phase separator) and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (eluent gradient: c-hexane/EtOAc 9:1 to c-hexane/EtOAc 1:1) afforded the title compound as a colorless wax. MS (LC/MS): 385.0 [M+H]+; tR (HPLC conditions k): 4.03 min.

1. stirringAfter stirring for 2 h
2. customthe reaction was quenched by addition of methanol (2 mL) and water with vigorous stirring
3. extractionThe mixture was extracted with CH2Cl2 (2×)
4. washthe combined organics were washed with brine
5. customdried (phase separator)
6. concentrationconcentrated under reduced pressure
7. customPurification by flash column chromatography on silica gel (eluent gradient: c-hexane/EtOAc 9:1 to c-hexane/EtOAc 1:1)