C([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Br:25])[CH:24]=1)[C@@H:9]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[F:18])O)(C)(C)C.C(OC(=O)N[C@H](C1C=C(F)C=CC=1F)[C@@H](C1C=NC=C(Br)C=1)O)(C)(C)C.CC(C)([O-])C.[K+].C(OCC)(=O)C>O1CCCC1.O>[Br:25][C:23]1[CH:24]=[C:19]([C@@H:8]2[C@@H:9]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[F:18])[O:26][C:6](=[O:5])[NH:7]2)[CH:20]=[N:21][CH:22]=1
A mixture of tert-butyl((1R,2R)-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)-2-hydroxyethyl)carbamate and tert-butyl((1R,2R)-2-(5-bromopyridin-3-yl)-1-(2,5-difluorophenyl)-2-hydroxyethyl)carbamate (about 6:1 ratio) (101 g, 236 mmol) in tetrahydrofuran (590 mL) was cooled to −7° C. with a methanol/ice bath. To this mixture was added a solution of 1 M potassium tert-butoxide in tetrahydrofuran (590 mL, 590 mmol) via an addition funnel while maintaining the internal temperature <3° C. The reaction mixture was stirred with a cooling bath for 30 min and then allowed to warm up to room temperature. After 20 h, the reaction was deemed complete by LC/MS. The reaction mixture was concentrated to dryness to give crude product. Another identical scale reaction was performed. The crude products of the two batches were combined to work up together. They were treated with ethyl acetate (1.75 L) and water (1.75 L). The layers were separated. The organic layer was washed with brine (1.75 L), dried (sodium sulfate), and evaporated to give 161.5 g of crude product as a brown solid. This was purified by ISCO to give 67.1 g (42% yield). LC/MS (ES+) 355/357 (M+H, 100; Br isotope pattern); 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J=2.2 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H), 7.97 (t, J=2.0 Hz, 1H), 7.29-7.23 (m, 1H), 7.18-7.09 (m, 2H), 6.40 (s, 1H), 5.56 (d, J=5.7 Hz, 1H), 4.84 (d, J=5.5 Hz, 1H); Calcd for C14H9N2BrF2O2: C, 47.34; H, 2.55; N, 7.86; Br, 22.50; F, 10.69. Found: C, 47.29; H, 2.61; N, 7.87; Br, 22.40; F, 10.37. Note: Chiral HPLC of the above sample showed 4.7% of the enantiomer. The (4S,5S) enantiomer can be purged by recrystallization from methanol to give >99.9 ee with 67% recovery.
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