Reaction Steps
A cooled (0° C.) solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid (R)-1-(7-vinyl-quinolin-2-yl)-ethyl ester (340 mg, 0.585 mmol) in anhydrous dichloromethane (20 mL) under nitrogen was treated with trimethylsilyl-trifluoromethanesulfonate (212 μL, 1.17 mmol). After stirring for 1.5 h at 0° C., the reaction was quenched with saturated sodium bicarbonate solution and stirred for 20 minutes. The organic layer was separated and washed with saturated sodium bicarbonate solution. The organics were dried over anhydrous sodium sulfate, filtered and evaporated. To the residue in anhydrous acetonitrile (15 mL) was added 4 Å molecular sieves (1 g) followed by a solution of (E)-(R)-2-cyclopropylmethyl-pent-3-enoic acid (108 mg, 0.702 mmol) in anhydrous acetonitrile (5 mL). N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (157 mg, 0.819 mmol) and 1-hydroxybenzotriazole (119 mg, 0.702 mmol) were then added and the resulting mixture stirred for 69 h. The reaction mixture was filtered through Celite with dichloromethane and the filtrate was washed with saturated aqueous ammonium chloride solution, water then brine. The organics were 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 0:1 to afford the title compound (142 mg, 39%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.03-0.12 (m, 2H), 0.37-0.45 (m, 2H), 0.63-0.71 (m, 1H), 0.87-0.94 6H), 1.30 (d, J=6.9 Hz, 3H), 1.45-1.66 (m, 2H), 1.71-1.74 (m, 6H), 1.92-1.95 (m, 1H), 2.02-2.09 (m, 1H), 2.12-2.20 (m, 1H), 2.75-2.87 (m, 1H), 2.93 (q, J=7.3 Hz, 1H), 3.58-3.68 (m, 1H), 3.81-3.91 (m, 1H), 4.27 (dd, J=8.5, 6.1 Hz, 1H), 4.45 (br d J=12.5 Hz, 1H), 5.28 (app pentet, J=6.9 Hz, 1H), 5.44 (br d J=10.9 Hz, 1H), 5.48-5.65 (m, 2H), 5.98 (d, J=17.6 Hz, 1H), 6.13 (q, J=6.7 Hz, 1H), 6.19-6.24 (m, 1H), 6.65 (br d, J=7.6 Hz, 1H), 6.93 (dd, J=17.5, 10.8 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.69 (dd, J=8.5, 1.3 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 8.04 (s, 1H), 8.18 (d, J=8.5 Hz, 1H). LCMS (m/z) 618.3 [M+H], Tr=3.07 min.
