Dimethylacetamide → 3-(4-(1H-1,2,4-Triazol-1-yl)benzyl)-6-((4-cyanophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-2-methoxyquinoline-4-carbonitrile

Participants

Reaction Conditions

Reaction Steps

A mixture containing 4-((3-(4-(1H-1,2,4-triazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)benzonitrile (150 mg, 0.267 mmol, Example 14a), zinc cyanide (56 mg, 0.48 mmol), tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol), zinc powder (5 mg, 0.08 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 26 mg, 0.05 mmol) and dimethylacetamide (1.4 mL, sparged with argon for 20 minutes) was heated to 120° C. After 2 hours, the flask was allowed to cool to 23° C. Ethyl acetate (20 mL) was added. The mixture was filtered through Celite®, rinsing with ethyl acetate. The filtrate was washed sequentially with saturated aqueous sodium bicarbonate solution (25 mL), water (25 mL), and saturated aqueous sodium chloride solution (25 mL). The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (4 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with dichloromethane initially, grading to 5% methanol-dichloromethane provided the title compound as an impure off-white solid. The impure solid was further purified by RP-HPLC eluting initially with 5% acetonitrile-water (containing 0.05% trifluoroacetic acid), grading to 95% acetonitrile-water (containing 0.05% trifluoroacetic acid) to provide the title compound as a white solid after partitioning the twice purified material between dichloromethane-saturated aqueous sodium bicarbonate solution, separating the layers, drying the organic layer with sodium sulfate, filtering the dried solution, and concentrating the filtrate to dryness. 1H NMR (500 MHz, CDCl3) δ ppm 8.47 (s, 1H), 8.16 (d, J=2.1 Hz, 1H), 8.05 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.68-7.63 (m, 2H), 7.61-7.45 (m, 7H), 7.35 (s, 1H), 6.38 (s, 1H), 4.93 (s, 1H), 4.38 (s, 2H), 4.11 (s, 3H), 3.37 (s, 3H); MS (ESI): mass calcd. for C32H24N8O2, 552.2. m/z found, 553.0 [M+H]+.

Provenance & Evidence