Reaction Steps
To a mixture of 49.3 g A2 (0.11 mol, 1.00 equiv.) and 29.3 g 4-fluoro-3-(trifluoromethyl)phenylacetic acid (0.13 mol, 1.20 equiv.) in 120 mL N,N-dimethylformamide, DMF, and 40 mL dichloromethane at room temperature was added 12 mL N-methylmorpholine, NMM (0.11 mol, 1.00 equiv.) and 14.9 g 1-hydroxybenzotriazole, HOBT (0.11 mol, 1.00 equiv.). To the solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, EDC (0.22 mol, 2.00 equiv.) in two equivalent portions at a 5 min. interval. The reaction mixture was stirred at room temperature for 16 h then taken-up in 800 mL ethyl acetate and washed with saturated aqueous sodium bicarbonate and aqueous brine six times. The organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo to afford a glassy solid. The product was purified by recrystallization from diethyl ether to yield 41 g of 1 as a colorless solid. 1H NMR (400 MHz; d6-DMSO; T=393 K): δ 0.92 (d, J=6.6 Hz, 6H), 0.95-1.20 (m, 2H), 1.35 (t, J=7.0 Hz, 3H), 1.32-1.50 (m, 2H), 1.50 (d, J=6.6 Hz, 3H), 1.58 (d, J=1.0 Hz, 1H), 1.85 (dd, J=10.3, 10.3 Hz, 1H), 1.99 (dd, J=11.4, 11.4 Hz, 1H), 2.52-2.68 (m, 2H), 2.75 (d, J=11.4 Hz, 1H), 2.88 (br s, 1H), 3.10 (dd, J=9.1, 14.8 Hz, 1H), 3.30 (dd, J=9.1, 13.7 Hz, 1H), 3.52 (br s, 1H), 4.09 (qt, J=7.0 Hz, 2H), 5.12 (qt, J=9.12 Hz, 1H), 7.00-7.13 (m, 2H), 7.18 (d, J=10.3 Hz, 1H), 7.30 (dd, J=10.3, 10.3 Hz, 1H), 7.33-7.48 (m, 3H), 7.57 (dd, J=9.5, 9.5 Hz, 1H), 7.72 (d, J=9.5 Hz, 1H), 7.87 (dd, J=9.5, 9.5 Hz, 1H), 8.15 (d, J=7.8 Hz, 1H) ppm; MS (ESI+) m/z=653.3 [M+H]+; Analytical calculated: 66.24%, C, 6.18% H, 11.64% F and 8.58% N. Found: 66.17% C, 6.05% H, 8.56% N, 11.59% F.
