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 79c), 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 50 mL ethyl acetate. 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 (500 MHz, CDCl3, 3:1 ratio of rotamers, * denotes minor rotamer) δ ppm 8.51 (d, J=2.0 Hz, 1H), 8.42* (d, J=2.0 Hz, 1H), 8.09-8.03 (m, 1H), 7.61 (s, 1H), 7.59-7.54 (m, 2H), 7.50-7.46* (m, 1H), 7.41 (dd, J=8.8, 2.0 Hz, 1H), 7.25-7.21 (m, 1H), 6.18 (s, 1H), 5.82* (s, 1H), 4.60-4.50 (m, 2H), 4.44-4.38* (m, 1H), 4.38-4.32* (m, 1H), 4.24-4.14 (m, 2H), 4.02* (dd, J=10.0, 5.8 Hz, 1H), 3.82-3.48 (m, 5H), 2.98-2.88 (m, 2H), 1.86 (s, 3H), 1.76* (s, 3H), 1.33-1.24 (m, 3H); MS (ESI): mass calcd. for C29H27F3N6O2, 548.2. m/z found, 549.2 [M+H]+. The enantiomeric purity of Example 37 was determined to be 100% and opposite that of Example 36 by chiral SFC (Chiralpak AD-H, 4.6×20 mm, 85% CO2, 15% ethanol containing 0.2% triethylamine).
