Reaction Steps
A stirred solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (692 mg, 1.3 mmol) in dry dichlormethane (39 mL) was cooled to 0° C. under nitrogen and then trimethylsilyl trifluoromethanesulfonate (578 mg, 471 μL, 2.6 mmol) was added. The reaction was stirred for 1 h and then quenched with saturated sodium bicarbonate solution. The organic layer was separated and washed with further saturated sodium bicarbonate solution (2×), dried over anhydrous sodium sulfate, filtered and evaporated. To the residue was added 4 Å molecular sieves (powdered, 1.3 g) and a solution of the crude 2-cyano-2-methyl-but-3-enoic acid (2 mmol) in dry acetonitrile (39 mL) followed by 1-hydroxybenzotriazole (containing 20% H2O) (307 mg, 1.82 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (349 mg, 1.82 mmol). The mixture was stirred for 3.5 h, filtered through Celite, washing with extra dichloromethane and the filtrate washed with saturated ammonium chloride solution, water then saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:1 to 1:3 to afford the title compound (356 mg, 51%) as a white solid as a mixture of diastereoisomers. 1H NMR (300 MHz, CDCl3) δ 0.90-0.97 (m, 3H), 0.99 (d, J=6.9 Hz, 3H), 1.33 (app t, J=7.1 Hz, 3H), 1.54-1.61 (m, 1H), 1.70-1.79 (m, 1H), 1.71 (s, 1.5H), 1.72 (s, 1.5H), 1.89-2.00 (m, 1H), 2.09-2.25 (m, 2H), 2.91-3.02 (m, 1H), 3.65-3.76 (m, 1H), 3.84 (d, J=11.2 Hz, 1H), 4.22-4.36 2H), 4.72 (d, J=12.1 Hz, 1H), 4.97 (dd, J=12.1 Hz, 2.5 Hz, 1H), 5.31-5.38 (m, 1H), 5.44 (t, J=9.8 Hz, 1H), 5.70 (dd, J=17.2, 10.3 Hz, 1H), 5.87-6.02 (m, 1H), 6.53-6.60 (m, 1H), 6.73-6.87 (m, 1H). LCMS (m/z) 538.0, 540.0, 542.0 [M+H], Tr=2.68 min.
