(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone → 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(1,2-dimethyl-1H-imidazol-5-yl)prop-2-yn-1-ol

Participants

Reaction Steps

To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (405 mg, 0.85 mmol, Intermediate 8: step b) was added THF (20 mL). The solution was cooled in a dry-ice bath and TMS-lithiumacetylide (0.5 M in Et20, 1.8 mL, 0.9 mmol) was introduced. After 60 minutes, additional TMS-lithiumacetylide (5.0 mL, 2.5 mmol, 0.5 M in Et2O) was added and the reaction mixture was stirred at room temperature overnight. After 24 hours, the reaction was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (4×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. Chromatography on silica gel (2% MeOH-DCM increasing to 5% 2 M NH3-MeOH) afforded the title compound and the silylated title compound. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=1.9 Hz, 1H), 7.84-7.68 (m, 2H), 7.44 (dd, J=43.2, 8.2 Hz, 5H), 6.67 (s, 1H), 4.34 (s, 2H), 4.07 (s, 3H), 3.37 (s, 3H), 2.77 (s, 1H), 2.32-2.12 (m, 3H); MS (ESI): mass calcd. for C26H21ClF3N3O2, 499.1, m/z found 500.1 [M+H]+. 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(1,2-dimethyl-1H-imidazol-5-yl)prop-2-yn-1-ol was purified by chiral chromatography (Chiralpak AD (20 μM) diacel (41 mm×41 mm), heptane:2-propanol with 2% isopropylamine (93:7)) to give 2 enantiomers. The first eluting enantiomer was Example 14b and the second eluting enantiomer was Example 14c.

Provenance & Evidence