Reaction Steps
Dimethylacetamide (5 mL, sparged with nitrogen gas) was added to a mixture containing 1-(3-((4-chloro-2-ethyl-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(hydroxy)(1-methyl-1H-1,2,3-triazol-5-yl)methyl)azetidin-1-yl)ethanone (200 mg, 0.358 mmol, Intermediate 79b), zinc cyanide (85 mg, 0.724 mmol), zinc powder (10 mg, 0.153 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 36 mg, 0.0755 mmol) and tris(dibenzylideneacetone)dipalladium (33 mg, 0.0360 mmol). The resulting heterogeneous mixture was heated to 120° C. After 6 hours, the mixture was cooled to 23° C. and diluted with ethyl acetate (50 mL). The mixture was filtered through Celite®, rinsing with ethyl acetate. Hexanes (25 mL) were added to the filtrate and the resulting solution was washed with water (2×30 mL) and saturated aqueous sodium chloride solution (25 mL). The washed solution was dried with sodium sulfate and the dried solution was filtered. Celite® (6 g) was added to the filtrate and the mixture was concentrated to provide a free-flowing powder. The powder was loaded onto a column for flash-chromatography purification. Elution with dichloromethane initially, grading to 10% methanol-dichloromethane provided an off white solid. The purified solid was dissolved in a minimal amount of acetonitrile-water and the resulting solution was lyophilized to provide the title compound as a white solid. 1H NMR (400 MHz, CDCl3, 3:1 mixture of rotamers, * denotes minor rotamer peaks) δ ppm 8.51 (d, J=2.1 Hz, 1H), 8.43* (d, J=2.0 Hz, 1H), 8.10-8.01 (m, 1H), 7.61 (s, 1H), 7.59-7.54 (m, 2H), 7.48* (dd, J=8.8, 2.0 Hz, 1H), 7.44-7.39 (m, 1H), 7.26-7.20 (m, 1H), 6.29 (s, 1H), 5.95* (s, 1H), 4.60-4.51 (m, 2H), 4.45-4.31 (m, 1H), 4.26-4.11 (m, 2H), 4.07-3.99* (m, 1H), 3.82-3.48 (m, 5H), 3.01-2.87 (m, 2H), 1.86 (s, 3H), 1.75* (s, 3H), 1.34-1.23 (m, 3H); MS (ESI): mass calcd. for C29H27F3N6O2, 548.2. m/z found, 549.1 [M+H]+. The enantiomeric purity of Example 36 was determined to be 99.5% by chiral SFC (Chiralpak AD-H, 4.6×20 mm, 85% CO2, 15% ethanol containing 0.2% triethylamine).
