Reaction Steps
A mixture of (3-benzyl-2,4-dichloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (523 mg, 0.960 mmol, Example 109), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (262 mg, 1.26 mmol), PdCl2(dppf) (71 mg, 0.097 mmol), K2CO3 (266 mg, 1.92 mmol), 1,4-dioxane (20 mL), and water (5 mL) was sparged with N2 for about 12 minutes, and then heated at 70° C. for 18 hours. After cooling to room temperature, the mixture was filtered through a syringe filter. The filtrate was concentrated, and the residue was partitioned between DCM and water. The organic layer was dried (Na2SO4), filtered, concentrated, and purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound as a TFA salt. 1H NMR (400 MHz, MeOH-d4) δ 9.05 (s, 1H), 8.85 (s, 1H), 8.38 (d, J=2.02 Hz, 1H), 8.16 (d, J=8.59 Hz, 1H), 8.11 (d, J=8.08 Hz, 1H), 7.86-7.94 (m, 2H), 7.76-7.86 (m, 1H), 7.71 (s, 1H), 7.24-7.32 (m, 2H), 7.18-7.23 (m, 1H), 7.14 (s, 1H), 7.03 (d, J=7.07 Hz, 2H), 4.58 (s, 2H), 3.90 (s, 3H), 3.73 (s, 3H). This TFA salt was neutralized by partitioning between saturated NaHCO3 aqueous solution and DCM. The organic layer was dried (Na2SO4), filtered, concentrated, and purified by chiral HPLC (Chiralcel OD, 85% heptanes/15% ethanol) to give two enantiomers which were further purified on a silica gel column (0-8% MeOH in DCM) to give the two compounds as white solids. The first eluting enantiomer, Example 111b, 1H NMR (400 MHz, CDCl3) δ 8.82-8.86 (m, 1H), 8.27 (d, J=2.02 Hz, 1H), 8.04 (d, J=9.09 Hz, 1H), 7.94 (d, J=8.59 Hz, 1H), 7.70 (s, 1H), 7.63-7.69 (m, 3H), 7.27-7.32 (m, 3H), 7.19-7.24 (m, 1H), 7.05 (d, J=7.07 Hz, 2H), 6.36 (s, 1H), 4.51 (s, 2H), 3.89 (s, 3H), 3.37 (s, 3H); MS m/e 589.2 [M+H]+. The second enantiomer to elute off chiral column, Example 111c, 1H NMR (400 MHz, CHLOROFORM-d) δ 8.84 (d, J=2.02 Hz, 1H), 8.28 (d, J=2.02 Hz, 1H), 8.04 (d, J=8.59 Hz, 1H), 7.94 (dd, J=2.02, 8.08 Hz, 1H), 7.70 (s, 1H), 7.63-7.69 (m, 3H), 7.27-7.32 (m, 3H), 7.19-7.24 (m, 1H), 7.05 (d, J=7.07 Hz, 2H), 6.36 (br. s., 1H), 4.51 (s, 2H), 3.89 (s, 3H), 3.38 (s, 3H); MS m/e 589.2 [M+H]+.
