反应详情

Trimethylsilyltrifluoromethanesulfonate (341 μL, 1.89 mmol) was added dropwise to a solution of the (S)-1-{(S)-2-tert-butoxycarbonylamino-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (670 mg, 1.05 mmol) in dichloromethane (15 mL) at 0° C. under N2 and the reaction was stirred for 85 minutes. To this was added N,N-diisopropylethylamine (730 μL, 4.19 mmol) and the reaction was warmed to room temperature. The volatiles were evaporated to afford a colourless foam which was dissolved in acetonitrile (15 mL). To this solution was added O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (477 mg, 1.26 mmol), (S)-2-tert-butoxycarbonylamino-3-(4-methoxy-phenyl)-propionic acid (340 mg, 1.15 mmol) and N,N-diisopropylethylamine (730 μL, 4.19 mmol) and the reaction was stirred for 18 h. The volatiles were evaporated and the residue partitioned between pH=7 buffer and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the volatiles evaporated. The residue was purified by silica chromatography using a gradient of iso-hexanes/ethyl acetate 3:1 to 1:1 to afford the title compound (570 mg, 67%) as a colourless foam. 1H NMR (300 MHz, CDCl3) δ0.18 (s, 6H), 1.00 (s, 9H), 1.43 (s, 9H), 1.45-1.60 (m, 2H) 1.73-1.83 (m, 1H), 1.85-1.95 (m, 1H), 2.30 (br s, 1H), 2.65-3.00 (m, 5H), 3.50 (d, J=11.2 Hz, 1H), 3.80 (s, 3H), 4.24-4.37 (m, 2H), 4.65 (d, J=11.8 Hz, 1H), 4.95 (d, J=11.8 Hz, 1H), 4.96-5.04 (m, 1H), 5.62-5.75 (m, 1H), 6.45 (d, J=8.3 Hz, 1H), 6.64-6.75 (m, 2H), 6.78-6.86 (m, 3H), 7.07-7.16 (m, 3H). LCMS (m/z) 817.3 [M+H], Tr=5.89 min.

1. customThe volatiles were evaporated
2. customto afford a colourless foam which
3. stirringthe reaction was stirred for 18 h
4. customThe volatiles were evaporated
5. customthe residue partitioned between pH=7 buffer
6. dry with materialThe organic layer was dried over anhydrous sodium sulfate
7. customthe volatiles evaporated
8. customThe residue was purified by silica chromatography