Reaction Steps
A suspension of (2S)-4-carbamoyl-2-{4-[(cyclopropanecarbonyl-amino)-methyl]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}-butyric acid (1.4 g, 3.8 mmol) in dry CH2Cl2 (87 mL) was cooled to −40° C. with IPA/dry ice bath. Thionyl chloride (0.5 g, 4.1 mmol) was added dropwise, followed by pyridine (0.3 g, 4.1 mmol). The mixture was stirred at −40° C. for 30 minutes. Triethylamine (0.4 g, 4.2 mmol) was added dropwise, and the mixture was stirred at −30 to −40° C. for 3 hours. The mixture was filtered into ice water (150 mL). The aqueous layer was extracted with CH2Cl2 (40 mL), and the combined CH2Cl2 solution was washed with H2O (2×40 mL) and brine (40 mL), and dried (MgSO4). Solvent was removed, and the solid was slurried with ethanol (20 mL) to give cyclopropanecarboxylic acid {2-((3S)-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (1.0 g, 74%) as a white solid: mp 219-221° C.; Chiral HPLC: Daicel ChiralPak AD, 46×250 mm, 70/30 IPA/hexane, 0.6 mL/min, 19.76 min (98.5% ee); 1H NMR (DMSO-d6) δ 0.69-0.72 (m, 4H), 1.61-1.71 (m, 1H), 2.04-2.08 (m, 1H), 2.50-2.63 (m, 2H), 2.83-2.97 (m, 1H), 4.74 (d, J=5.7 Hz, 2H, CH2), 5.11-5.18 (dd, J=5.2 and 12.4 Hz, 1H, CH), 7.67-7.88 (m, 3H, Ar), 8.69 (t, J=5.6 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 6.41, 13.50, 21.96, 30.91, 37.74, 48.84, 121.84, 127.08, 131.51, 133.31, 134.76, 139.39, 166.92, 167.44, 169.78, 172.72, 173.09; Anal. calcd. for C18H17N3O5: C, 60.84; H, 4.82; N, 11.82. Found: C, 60.49; H, 4.76; N, 11.51.
