反应详情

To a solution of (S)-1-((S)-2-tert-butoxycarbonylamino-3-phenyl-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (1.0 g, 2.0 mmol) in anhydrous dichloromethane (7 mL) at 0° C. and under an atmosphere of nitrogen was added trifluoroacetic acid (1.5 mL, 19.7 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h before concentrating in vacuo. The residue was dissolved in anhydrous acetonitrile (11 mL), cooled to 0° C. and under an atmosphere of nitrogen was added N,N-diisopropylethylamine (1.8 mL, 9.8 mmol), N-Boc-Val-OH (428 mg, 2.0 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.1 g, 2.8 mmol). After 16 h at room temperature the reaction was diluted with ethyl acetate and quenched with hydrochloric acid (1 M). The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and brine. 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 to give the title compound (1.0 g, 84%) as a viscous oil. 1H NMR (300 MHz, CDCl3) δ 0.89 (d, J=6.7 Hz, 3H), 0.95 (d, J=6.9 Hz, 3H), 1.47 (s, 9H), 1.47-1.56 (m, 1.72-1.94 (m, 2H), 2.08-2.20 (m, 1H), 2.23-2.36 (m, 1H), 2.67-2.84 (m, 1H), 2.91 (dd, J=12.9, 9.4 Hz, 1H), 3.05 (dd, J=12.9, 5.4 Hz, 1H), 3.53 (d, J=10.9 Hz, 1H), 3.90-4.03 (m, 1H), 4.23-4.36 (m, 1H), 4.70, 4.84 (ABq, J=12.0 Hz, 2H), 5.00-5.14 (m, 1H), 5.73-5.86 (m, 1H), 6.55 (d, J=8.3 Hz, 1H), 7.16-7.34 (m, 5H). LCMS (m/z) 607.1 [M+H], Tr=3.24 min.

1. concentrationbefore concentrating in vacuo
2. dissolutionThe residue was dissolved in anhydrous acetonitrile (11 mL)
3. temperaturecooled to 0° C. and under an atmosphere of nitrogen
4. customquenched with hydrochloric acid (1 M)
5. customThe organic layer was separated
6. washwashed with a saturated aqueous solution of sodium bicarbonate and brine
7. customThe organic layer was then dried through a hydrophobic frit
8. concentrationconcentrated in vacuo
9. customThe residue was purified by silica gel chromatography