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 2,2,2-trichloro-ethyl ester (98.9 mg, 0.186 mmol) in dichloromethane (10 mL) was treated with trimethylsilyl-trifluoromethanesulfonate (70 μL, 0.372 mmol). After stirring at 0° C. for 60 min, the reaction was quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The combined organics were filtered through a phase separator and the volatiles were removed in vacuo to provide (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester as a white solid. To the white solid was added a solution of (E)-(R)-2-(tert-butyl-dimethyl-silanyloxymethyl)-4-[7-((R)-1-hydroxy-ethyl)-naphthalen-2-yl]-2-methyl-but-3-enoic acid (77.1 mg, 0.186 mmol) in anhydrous acetonitrile (10 mL) and the solution was cooled to 0° C. then treated with N,N-diisopropylethylamine (130 μL, 0.744 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (85 mg, 0.223 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, washed with a saturated solution of sodium bicarbonate, 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 1:4 to provide the title compound (48.0 mg, 31%) as a yellow gum. 1H NMR (300 MHz, CDCl3) δ 0.11-0.16 (m, 6H), 0.95 (s, 9H), 1.20-1.35 (m, 9H), 1.43 (s, 3H), 1.60 (d, J=6.4 Hz, 3H), 1.66-1.79 (m, 2H), 1.88-1.97 (m, 1H), 2.13-2.29 (m, 2H), 3.63-3.73 (m, 1H), 3.78-3.85 (m, 2H), 3.92 (d, J=10.0 Hz, 1H), 4.30-4.44 (m, 2H), 4.72 (d, J=12.0 Hz, 1H), 4.95 (d, J=12.0 Hz, 1H), 5.02-5.13 (m, 1H), 5.25-5.36 (m, 1H), 6.56 (d, J=16.5 Hz, 1H), 6.69-6.78 (m, 2H), 7.34 (d, J=8.5 Hz, 1H), 7.48 (dd, J=8.5, 1.3 Hz, 1H), 7.59 (dd, J=8.7, 1.6 Hz, 1H), 7.69-7.83 (m, 4H). LCMS (m/z) 829.4/827.4 [M+H], Tr=3.88 min.
