反应详情

To (S)-1-((S)-2-tert-butoxycarbonylamino-3-pyrazol-1-yl-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (730 mg, 1.47 mmol) in anhydrous dichloromethane (3 mL) at 0° C. and under an atmosphere of nitrogen was added trifluoroacetic acid (1.1 mL, 14.7 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h before concentrating in vacuo. The residue was dissolved in anhydrous acetonitrile (7 mL) at room temperature and under an atmosphere of nitrogen was added N,N-diisopropylethylamine (1.3 mL, 7.3 mmol), N-(tert-Butoxycarbonyl)-L-valine (319 mg, 1.5 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (782 mg, 2.1 mmol). Following 16 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 1:2 then 1:3 to give the title compound (460 mg, 52%) as a viscous clear oil, as a 2:1 mixture of diastereoisomers. LCMS (m/z) 599.1 [M+H], Tr=2.83 min.

1. concentrationbefore concentrating in vacuo
2. dissolutionThe residue was dissolved in anhydrous acetonitrile (7 mL) at room temperature and under an atmosphere of nitrogen
3. waitFollowing 16 h at room temperature
4. temperaturethe reaction was cooled to 0° C.
5. customquenched with 1 M hydrochloric acid
6. customThe organic layer was separated
7. washwashed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×)
8. customThe organic layer was then dried through a hydrophobic frit
9. concentrationconcentrated in vacuo
10. customThe residue was purified by silica gel chromatography