Reaction Steps
(R)-2-(4-Chlorophenylsulfonamido)-5,5,5-trifluoropentanamide (3.444 kg), potassium carbonate (2.774 kg), tetrabutylammonium bromide (0.484 kg), and 4-(bromomethyl)-3-fluorobenzonitrile (2.092 kg) were charged to a reactor. Ethyl acetate (17.2 L) and water (3.44 L) were then charged and the batch was heated to 50° C. until complete by HPLC (<1 relative AP starting material). The reaction is usually complete in about 15 hours. The batch was cooled to 15-20° C. and water (6.88 L) was charged and the bottom aqueous phase was separated. A solution of sodium phosphate monobasic (0.2 M in water, 20.66 L) was charged and the bottom aqueous phase was separated and the pH was tested to ensure that it was <6.5. (Note: If the pH is >6.5, an additional 20.66 L of 0.2 M sodium phosphate monobasic solution may be charged and the extraction and pH measurement repeated.) The solvent was then exchanged by a constant volume vacuum distillation. The reactor was placed under vacuum (270 mmHg) and the jacket was heated to 75-80° C. Once distillation of ethyl acetate started, isopropanol (41.34 L) was added at the same rate of distillate collection, and the overall batch volume was maintained at a constant level. Once all of the isopropanol was added, the vacuum was released and water (13.76 L) was charged. The batch temperature was maintained at approximately 50° C. during the water addition. The batch was then cooled to 15-20° C. and filtered. The wet cake was washed with 50% (v/v) aqueous isopropanol (4×21.6 kg) and then dried under vacuum at 50° C. to give the title compound as an off-white solid (3.648 kg, 78% yield.) 1H NMR (300 MHz, DMSO-d6) δ ppm 1.42-1.55 (m, 1 H) 1.80-1.93 (m, 1 H) 2.00-2.15 (m, 2 H) 4.44 (dd, J=7.91, 1.13 Hz, 1 H) 4.68 (d, J=17.71 Hz, 1 H) 4.99 (d, J=17.71 Hz, 1 H) 7.26 (s, 1 H) 7.50 (s, 1 H) 7.63-7.73 (m, 4 H) 7.78-7.87 (m, 3 H). 13C NMR (75 MHz, DMSO-d6) ppm 22.58-22.97 (m, 1 C) 29.96 (d, J=29.09 Hz, 1 C) 41.46 (d, J=5.49 Hz, 1 C), 57.86, 110.97, 111.45 (d, J=10.43 Hz, 1 C), 117.58, 119.11 (d, J=25.80 Hz, 1 C), 124.89, 128.53, 128.56, 129.21, 131.17, 131.98, 137.44, 138.32, 158.99 (d, J=247.54 Hz, 2 C), 170.25. 19F NMR, (CDCl3, 282 MHz) δ: −116.5, −65.9. IR (KBr): 3443, 3342, 3210, 2955, 2245, 1699, 1577, 1476, 1163 cm−1.
