3-(4-(1H-Pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline → (3-(4-(1H-Pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanol

Participants

Reaction Steps

A solution of n-BuLi (2.5 M in hexanes, 0.28 mL, 0.7 mmol) was added dropwise by syringe to a solution of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (0.303 g, 0.707 mmol, Intermediate 10) in dry THF (7 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (1-methyl-1H-imidazol-5-yl)(pyridin-2-yl)methanone (0.144 g, 0.769 mmol, Intermediate 33: step b) in dry THF (0.5 mL) was added dropwise. The reaction was stirred for 5 minutes, switched to an ice bath for 10 minutes, then removed from the cold bath and allowed to warm to ambient temperature. The reaction was quenched with methanol. The mixture was partitioned between water and ethyl acetate. The separated aqueous phase was further extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 100% EtOAc) followed by reverse-phase chromatography (acetonitrile/H2O+0.05% TFA). The isolated product fractions were basified with saturated aqueous sodium bicarbonate, extracted with DCM, dried (Na2SO4), filtered, and concentrated to dryness. Impurities remained in the sample, therefore the product was taken forward to the chiral separation step.

Provenance & Evidence