Reaction Steps
To a stirred mixture of 3′-methyl-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxylic acid (described in Intermediate 1, 20 mg, 0.077 mmol), (3S,5S,6R)-3-amino-6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-2-one hydrochloride (described in Intermediate 5, 22 mg, 0.058 mmol), HOBT (12 mg, 0.078 mmol), and EDC (15 mg, 0.078 mmol) in DMF (0.5 mL) was added N,N-diisopropylethylamine (0.031 mL, 0.175 mmol), and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH:NH4OH 100:0:0 to 90:10:1, to give the desired product as a mixture of isomers. Separation of the stereoisomers was achieved by SFC using a ChiralPak IC column, eluting with CO2:MeOH:Et2NH—75:25:0.1, to give (6S)-3′-methyl-N-[(3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxamide, which was the first major peak to elute, and the title compound, which was the second major peak to elute. HRMS: m/z=584.1715 (M+1), calculated m/z=584.1727 for C26H24F6N5O4. 1H NMR (500 MHz, CD3OD) δ 8.87 (s, 1H), 8.14 (s, 1H), 7.28 (qd, 1H, J=9.0, 4.6 Hz), 7.02 (m, 1H), 4.79 (m, 1H), 4.54 (dd, 1H, J=11.7, 6.8 Hz), 4.02 (m, 1H), 3.93 (m, 1H), 3.68 (dq, 1H, J=15.4, 8.8 Hz), 3.55 (d, 1H, J=18.1 Hz), 3.54 (d, 1H, J=17.6 Hz), 3.40 (d, 2H, J=17.8 Hz), 3.20 (m, 1H), 2.72 (s, 3H), 2.34 (m, 1H), 1.33 (d, 3H, J=6.4 Hz).
