CCN(CC)CC.C(OC([N:15]1[CH2:19][C:18]([F:21])([F:20])[C:17]([CH3:23])([CH3:22])[C@H:16]1[C:24]([OH:26])=O)=O)(C)(C)C.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:24]([C@@H:16]1[C:17]([CH3:22])([CH3:23])[C:18]([F:20])([F:21])[CH2:19][NH:15]1)=[O:26]NEt3 (75.2 g, 743 mmol) was slowly added to a 10° C. solution of (2S)-4,4-difluoro-3,3-dimethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (98.3 g, 352 mmol), chlorodiphenylphosphate (101 g, 376 mmol), and ethyl acetate (1.0 L). The mixture was warmed to ambient temperature for 45 min., and was then cooled to 10° C. 2,2,2-Trifluoroethylamine (39.5 g, 399 mmol) was slowly added and the resultant mixture was stirred at ambient temperature for 2.75 h. 20% Aqueous citric acid (1.0 L) was added and the resulting layers were separated. The aqueous fraction was extracted with ethyl acetate (2×300 mL). The combined organic fractions were washed with saturated aqueous NaHCO3 (2×500 mL), and then with saturated aqueous NaCl (300 mL). The resulting organic fraction was concentrated to a weight of 900 g using a rotary evaporator. A 3 N HCl/ethyl acetate solution (500 mL) was added to the concentrate, and the mixture was stirred at ambient temperature for 24 h. The resulting solid was filtered, washed with ethyl acetate (100 mL), and was then dried in a vacuum oven at 55° C. to provide 98.0 g (93.9%) of (2S)-4,4-difluoro-3,3-dimethyl-pyrrolidine-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide; hydrochloride as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.46 (br s, 2H), 9.50 (t, J=6.2Hz, 1H), 4.17–4.33 (m, 2H), 3.68–4.02 (m, 3H), 1.23 (app d, J=2.1 Hz, 3H), 0.97 (app d, J=2.0 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 165.6, 127.9 (dd, JCF=250.2, 257.2 Hz), 125.6 (q, JCF=279.0 Hz), 64.8, 48.2 (t, JCF=33.4 Hz), 45.7 (t, JCF=21.2 Hz), 18.2 (d, JCF=7.5Hz), 17.2 (app dd, JCF=2.3, 5.8 Hz); MS (CI) m/z 261.1015 (261.1026 calcd for C9H14N2OF5, M−HCl+H+).
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