反应详情

温度

0 °C

To (S)-1-[(S)-2-tert-butoxycarbonylamino-3-(3-methyl-oxetan-3-ylmethoxy)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (1.2 g, 2.26 mmol) in anhydrous dichloromethane (10 mL) at 0° C. and under an atmosphere of nitrogen was added trifluoroacetic acid (1.7 mL, 22.6 mmol). The reaction mixture was stirred for 3 h before concentrating in vacuo and co-evaporating from toluene (1×). The residue was dissolved in anhydrous acetonitrile (24 mL) at room temperature and under an atmosphere of nitrogen was added N,N-diisopropylethylamine (2.0 mL, 11.3 mmol), N-(9-fluorenylmethoxycarbonyl)-L-valine (767 mg, 2.26 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.2 g, 3.2 mmol). Following 2 h at room temperature 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 1:2 to give the title compound (1.4 g, 82%) as a viscous clear oil. 1H NMR (300 MHz, CDCl3) δ 0.89-1.07 (m, 6H), 1.23 (s, 3H), 1.54-1.95 (m, 5H), 2.10-2.23 (m, 1H), 3.29-3.48 (m, 3H), 3.52-3.62 (m, 1H), 3.72-4.00 (m, 3H), 4.20-4.30 (m, 2H), 4.31-4.44 (m, 4H), 4.48 (d, J=5.6 Hz, 1H), 4.54 (d, J=5.6 Hz, 1H), 4.69 (d, J=12.3 Hz, 1H), 4.94 (d, J=12.3 Hz, 1H), 5.44-5.54 (m, 1H), 5.71-5.82 (m, 1H), 6.76 (d, J=7.6 Hz, 1H), 7.30-7.37 (m, 2H), 7.38-7.46 (m, 2H), 7.57-7.67 (m, 2H), 7.75-7.82 (m, 2H). LCMS (m/z) 753.2 [M+H], Tr=3.34 min.

1. concentrationbefore concentrating in vacuo and co-evaporating from toluene (1×)
2. dissolutionThe residue was dissolved in anhydrous acetonitrile (24 mL) at room temperature and under an atmosphere of nitrogen
3. waitFollowing 2 h at room temperature
4. customquenched with 1 M hydrochloric acid
5. customThe organic layer was separated
6. washwashed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×)
7. customThe organic layer was then dried through a hydrophobic frit
8. concentrationconcentrated in vacuo
9. customThe residue was purified by silica gel chromatography