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 methyl ester (257.4 mg, 0.621 mmol) in dichloromethane (15 mL) was treated with trimethylsilyl-trifluoromethanesulfonate (230 μL, 1.242 mmol). After stirring at 0° C. for 50 min, the reaction mixture was treated with N,N-diisopropylethylamine (430 μL, 2.484 mmol) and the volatiles were removed in vacuo. To the white solid was added a solution of (E)-(R)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-but-3-enoic acid (275.5 mg, 0.621 mmol) in acetonitrile (15 mL) and the solution was cooled to 0° C. then treated with N,N-diisopropylethylamine (430 μL, 2.484 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (283.4 mg, 0.745 mmol). After stirring at room temperature for 20 h, the reaction was quenched with hydrochloric acid (1 M, 20 mL). The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:3 to 0:1 to afford a yellow gum that was dissolved in ethyl acetate and washed with saturated sodium bicarbonate. The organics were then dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo to provide the title compound (319.4 mg, 69%) as a yellow glass. 1H NMR (300 MHz, CDCl3) δ 0.04 (s, 9H), 0.83-1.01 (m, 8H), 1.21-1.34 (m, 4H), 1.43 (s, 3H), 1.56-1.76 (m, 5H), 1.82-1.95 (m, 1H), 1.99-2.11 (m, 1H), 2.18 (s, 3H), 2.23-2.41 (m, 2H), 2.73-2.88 (m, 1H), 3.48-3.57 (m, 1H), 3.59-3.66 (m, 2H), 3.69-3.81 (m, 4H), 4.07-4.17 (m, 1H), 4.33-4.43 (m, 2H), 5.31 (app pentet, J=7.1 Hz, 1H), 6.06 (q, J=6.7 Hz, 1H), 6.73 (ABq, ΔδAB=0.06, JAB=16.3 Hz, 2H), 6.86 (d, J=7.6 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.62 (dd, J=8.5, 1.3 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 8.02 (s, 1H), 8.11 (d, J=8.7 Hz, 1H). LCMS (m/z) 740.4 [M+H], Tr=3.41 min.
