Difluoroacetic acid → (5S)-2,2-Difluoro-N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide

Temperature

2.5 °C

A suspension of (5S)-5-Aminomethyl-3-(3-fluoro-4-iodo-phenyl)-oxazolidin-2-one (1022, 5.0 g, 14.88 mmol) in methylene chloride (CH2Cl2, 50 mL) was treated with difluoroacetic acid (2.14 g, 1.41 mL, 22.32 mmol, 1.5 equiv) and N,N-diisopropylethylamine (DIEA or Hunig's base, 3.85 g, 5.18 mL, 29.76 mmol, 2.0 equiv), and the resulting reaction mixture was cooled down to 0-5° C. before being treated with EDCI (4.30 g, 22.32 mmol, 1.5 equiv) at 0-5° C. The reaction mixture was subsequently stirred at 0-5° C. for 1 h before being gradually warmed up to room temperature for 12 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (50 mL) and CH2Cl2 (50 mL). The two layers were then separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed H2O (50 mL) and the saturated aqueous NaCl solution (50 mL), dried over MgSO4, and concentrated in vacuo to afford the crude (5S)-2,2-difluoro-N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1026, 5.64 g, 6.16 g theoretical, 91.6%) as off-white powders, which by HPLC/MS and 1H NMR was found to be essentially pure and was directly used in the subsequent reactions without further purification. For 1026: 1H NMR (300 MHz, DMSO-d6) δ 3.54 (t, 2H, J=5.5 Hz), 3.77 (dd, 1H, J=6.3, 9.2 Hz), 4.15 (t, 1H, J=9.2 Hz), 4.77-4.86 (m, 1H), 6.25 (t, 1H, J=53.52 Hz, —CHCF2), 7.18 (dd, 1H, J=2.4, 8.7 Hz), 7.55 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (t, 1H, J=8.5 Hz), 9.19 (t, 1H, J=5.5 Hz, —CONH); C12H10F3IN2O3, LCMS (EI) m/e 415 (M++H), 456 (M++H+CH3CN).

1. customthe resulting reaction mixture
2. temperaturebefore being gradually warmed up to room temperature for 12 h
3. customthe reaction mixture was quenched with H2O (50 mL) and CH2Cl2 (50 mL)
4. customThe two layers were then separated
5. extractionthe aqueous layer was extracted with CH2Cl2 (2×50 mL)
6. washThe combined organic extracts were washed H2O (50 mL)
7. dry with materialthe saturated aqueous NaCl solution (50 mL), dried over MgSO4
8. concentrationconcentrated in vacuo

ORD record

ord-8aefc6ca48774e52a212cacf596e57f0

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08796465B2