反应详情

To (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-pyrazol-1-yl-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (450 mg, 0.75 mmol) in anhydrous dichloromethane (1 mL) at 0° C. and under an atmosphere of nitrogen was added trifluoroacetic acid (0.58 mL, 7.6 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h before concentrating in vacuo and co-evaporating from toluene. This residue was dissolved in anhydrous acetonitrile (7.5 mL) and at 0° C. and under an atmosphere of nitrogen was added (E)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoic acid (246 mg, 0.75 mmol), N,N-diisopropylethylamine (0.66 mL, 3.76 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (401 mg, 1.05 mmol). The solution was warmed to room temperature and stirred for 2 h. The reaction was cooled to 0° C., diluted with ethyl acetate and quenched with 1 M hydrochloric acid. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×). The organic layer was then dried through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 1:1 then 0:1 to give the title compound (433 mg, 72%) as a viscous clear oil, as a 2:1 mixture of diastereoisomers. LCMS (m/z)=806.3 [M+H], Tr=2.91 min.

1. concentrationbefore concentrating in vacuo and co-evaporating from toluene
2. dissolutionThis residue was dissolved in anhydrous acetonitrile (7.5 mL) and at 0° C. and under an atmosphere of nitrogen
3. temperatureThe solution was warmed to room temperature
4. stirringstirred for 2 h
5. temperatureThe reaction was cooled to 0° C.
6. customquenched with 1 M hydrochloric acid
7. customThe organic layer was separated
8. washwashed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×)
9. customThe organic layer was then dried through a hydrophobic frit
10. concentrationconcentrated in vacuo
11. customThe residue was purified by silica gel chromatography