Reaction Steps
To a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-6-iodo-2-methoxyquinoline (579 mg, 1.22 mmol, Intermediate 4: step e) in THF (5 mL) at −78° C. under argon was added n-butyllithium (1.6 M in hexane, 0.725 mL, 1.16 mmol) over 1 minute. The resulting dark brown solution was stirred for 1 minute before addition of a solution of (1-methyl-1H-imidazol-5-yl)(tetrahydro-2H-pyran-4-yl)methanone (237 mg, 1.22 mmol, Intermediate 1: step b) in THF (4 mL). The resulting orange solution was stirred at −78° C. for 5 minutes, then was transferred to an ice bath and stirred 30 minutes. The reaction was quenched by the addition of saturated aqueous NH4Cl, diluted with water and extracted with EtOAc (3×). The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The residue was purified by flash column chromatography (0-6% MeOH-DCM) to afford the title compound. MS m/e 544.2 [M+H]+. Example 1a was purified by chiral HPLC (Chiralcel OD-H, 20% EtOH-heptane) to give 2 enantiomers. The second enantiomer to elute was then further purified on a silica gel column (0-5% MeOH-DCM). Example 1b: (first enantiomer to elute off chiral column) 1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 8.09 (d, J=2.53 Hz, 1H), 7.75 (d, J=8.59 Hz, 1H), 7.66 (d, J=2.02 Hz, 1H), 7.56 (d, J=8.59 Hz, 2H), 7.43-7.52 (m, 2H), 7.34 (d, J=8.59 Hz, 2H), 7.24 (s, 1H), 6.38-6.54 (m, 1H), 4.28 (s, 2H), 4.05 (s, 3H), 4.00 (dd, J=3.28, 11.37 Hz, 1H), 3.79 (dd, J=3.54, 11.12 Hz, 1H), 3.54 (t, J=11.12 Hz, 1H), 3.32-3.37 (m, 1H), 3.30 (s, 3H), 2.46-2.61 (m, 1H), 2.07 (d, J=13.64 Hz, 1H), 1.57-1.75 (m, 1H), 1.39 (qd, J=4.55, 12.63 Hz, 1H), 0.95 (d, J=13.14 Hz, 1H); MS m/e 544.1 [M+H]+ and Example 1c: (second enantiomer to elute off chiral column) 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.86 (d, J=2.02 Hz, 1H), 7.76 (d, J=8.59 Hz, 1H), 7.69 (s, 1H), 7.57 (d, J=8.59 Hz, 2H), 7.36-7.46 (m, 3H), 7.32 (s, 1H), 7.21 (s, 1H), 6.43 (s, 1H), 4.32 (s, 2H), 4.03-4.14 (m, 4H), 3.90 (dd, J=3.28, 11.37 Hz, 1H), 3.52 (t, J=11.12 Hz, 1H), 3.33 (t, J=11.37 Hz, 1H), 3.25 (s, 3H), 2.42-2.54 (m, 1H), 2.36 (s, 1H), 2.12 (d, J=13.64 Hz, 1H), 1.42 (qd, J=4.29, 12.72 Hz, 1H), 1.21-1.35 (m, 1H), 1.03 (d, J=13.14 Hz, 1H); MS m/e 544.2 [M+H]+.
