5-bromo-1,2-dimethyl-1H-imidazole → (4-Chloro-3-(4-fluorobenzyl)-2-methoxyquinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)(2,6-dimethylpyridin-3-yl)methanol

Participants

Reaction Steps

A solution of n-BuLi (2.5 M in hexanes, 0.90 mL, 2.2 mmol) was added dropwise by syringe to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (408.9 mg, 2.336 mmol) in dry THF (12 mL) in a dry ice-acetone bath. After 1-2 minutes, (4-chloro-3-(4-fluorobenzyl)-2-methoxyquinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone (0.505 g, 1.16 mmol, Intermediate 48: step b) in dry THF (12 mL) was added to the mixture via syringe. After 5 minutes, the reaction was removed from the cold bath and was allowed to warm to ambient temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride. Water was added and the aqueous mixture was extracted with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM). Due to remaining impurities, the material was dissolved in ethyl acetate and washed several times with minimal water. The organic layer was dried (Na2SO4), filtered, and concentrated to dryness. The material was purified by reverse phase chromatography (acetonitrile/H2O+0.05% TFA), basified with saturated aqueous sodium bicarbonate, and extracted with DCM, before being dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J=2.2 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.37 (dd, J=8.6, 2.2 Hz, 1H), 7.28-7.24 (m, 2H), 7.11 (d, J=8.0 Hz, 1H), 6.96-6.89 (m, 3H), 6.00 (s, 1H), 4.23 (s, 2H), 4.07 (s, 3H), 3.36 (s, 3H), 2.51 (s, 3H), 2.40 (s, 3H), 2.30 (s, 3H); MS m/e 531.2 [M+H]+.

Provenance & Evidence