Reaction Steps
1-(5-Bromo-4-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.096 g, 0.188 mmol), (3-fluorophenyl)boronic acid (0.039 g, 0.282 mmol), potassium carbonate (0.078 g, 0.564 mmol), and Pd(PPh3)4 (0.022 g, 0.019 mmol) were combined in 1,4-dioxane (0.705 ml) and water (0.235 ml). The reaction was heated to 90° C. for 2 h. The reaction was cooled to RT and sat. aq. ammonium chloride was added. The organics were extracted (×3) with DCM, dried through a Radley's phase separator, and concentrated in vacuo. The crude material was purified via MPLC, eluting with 0-100% ethyl acetate in heptanes, to yield 1-(6-chloro-3′-fluoro-4-methoxy-[1,1′-biphenyl]-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.025 g, 0.048 mmol, 25.3% yield) as a white solid. m/z (ESI) 526.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3 H) 6.44 (d, J=1.76 Hz, 1 H) 6.80 (d, J=9.54 Hz, 1 H) 6.93 (d, J=9.12 Hz, 1 H) 7.21-7.36 (m, 3 H) 7.54 (d, J=12.96 Hz, 2 H) 7.85 (dd, J=8.97, 2.13 Hz, 1H) 8.22 (d, J=9.64 Hz, 1 H) 8.36 (d, J=1.97 Hz, 1 H) 8.72 (s, 1 H) 11.49-11.64 (m, 1 H) 11.67 (s, 1 H). 1-(6-chloro-3′-fluoro-4-methoxy-[1,1′-biphenyl]-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide was separated by chiral SFC on a (S,S) Whelk-O column, eluting with 40% methanol to yield (P)-1-(6-chloro-3′-fluoro-4-methoxy-3-biphenylyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide as peak 1 and (M)-1-(6-chloro-3′-fluoro-4-methoxy-3-biphenylyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide as peak 2. Data for peak 1: m/z (ESI) 526.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.75 (s, 3 H) 6.14 (d, J=0.93 Hz, 1 H) 6.69 (d, J=9.64 Hz, 1 H) 6.73 (d, J=8.81 Hz, 1 H) 7.18-7.26 (m, 1 H) 7.29-7.34 (m, 2 H) 7.43-7.55 (m, 3 H) 7.74 (dd, J=8.81, 1.97 Hz, 1 H) 8.09-8.29 (m, 4 H). Data for peak 2: m/z (ESI) 526.0 (M+H)+. 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.75 (s, 3 H) 6.08-6.15 (m, 1 H) 6.68 (d, J=9.64 Hz, 1H) 6.72 (d, J=8.71 Hz, 1 H) 7.16-7.26 (m, 1 H) 7.27-7.35 (m, 2 H) 7.41-7.55 (m, 3 H) 7.73 (dd, J=8.71, 1.97 Hz, 1 H) 8.08-8.25 (m, 4 H).
