Carbamate → 3-(4-Bromo-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one, (R)-

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Reaktionsschritte

To a solution of 1056 g (3.64 mol) of 2-Methylpropyl (4-bromo-3-fluorophenyl)carbamate in 6.65 L of THF cooled to −15° C. in a 22 L round bottom flask was added a solution of 428 g (4.55 mol, 1.25 equiv.) of lithium t-amylate over 10 min via an addition funnel, maintaining −15° to −12° C. In a separate 5 L flask, a solution of 438 g (4.37 mol, 1.20 equiv.) of (S)-3-chloro-1,2-propanediol in 1.75 L of THF was cooled to −25° C. and treated with a 20% t-BuOK solution in THF (2645 mL, 4.29 mol, 1.18 equiv) over 25 min, resulting in a thick but stirrable slurry. This was allowed to warm to 10° over 75 min and then poured into the 22 L flask containing the carbamate solution. The resulting slurry was allowed to warm from −7° to 7° over 1.5 h, monitoring reaction progress by HPLC. Upon completion (˜2.5% each of remaining 2-Methylpropyl (4-bromo-3-fluorophenyl)carbamate and the over addition product) a quench solution composed of 1.05 AcOH and 3.5 L of water was added. The layers were separated. The aqueous layer was back-extracted with 1 L of THF, and the combined organic layers were washed with brine. The volatile were removed, giving white solids wet with acetic acid. This material was slurried in 1.6 L of EtOAc. Hexane (4L) was added over 1 h. The resulting slurry was cooled to 2° over 1 h and filtered, giving 916 g (87%) of (5R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one as coarse white crystals: TLC Rf=0.008 (50% EtOAc/hexane); HPLC rt=2.55 min; mp 114-121 °; [α]D=+52.2° c=1, MeOH); 1H NMR (DMSO) δ7.49 (m, 2H), 7.15 (d,1H, J=8.5 Hz), 5.30 (br s, 1H), 4.54 (m, 1H), 3.89 (t, 1H, J=8.6 Hz), 3.67 (m, 1H), 3.50 (dd, 1H, J=3.0, 11.8 Hz), 3.39 (dd, 1H, 3.8, 11.8 Hz); 13C NMR (DMSO) δ158.1 (s, JCF=241 hz), 154.2 (S), 139.7 (S, JCF=10 hz), 133.3 (D), 114.9 (D), 105.9 (d, JCF=29 Hz), 100.9 (s, JCF=21 Hz), 73.3(d), 61.5(t), 45.9 (t); Anal. calc'd for C10H9BrFNO3: C, 41.40; H, 3.13; N, 4.83: Br, 27.55; found: C, 41.11; H, 3.06; N, 4.83: Br, 26.97.

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