Triethylamine → (R)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(1,1,2,2-tetrafluoroethoxy)benzene

A solution of acetic anhydride (10 mL, 106 mmol) and formic acid (6 mL, 159 mmol) was heated at 60° C. for 3 h, then cooled to rt. An aliquot of the resulting solution (0.623 mL) was added to a solution of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine prepared as described in Procedure 3, 4, 5 and 6 (83 mg, 0.2 mmol) in DCE (1 mL). The reaction mixture was stirred at rt for 1.5 h, then concentrated under reduced pressure to yield a clear oil. The resulting oil was dissolved in DCM and purified by ISCO chromatography (12 g) with 0-30% EtOAc in hexane to yield (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)formamide as white solid (72 mg, 81% yield). LCMS: RT=2.02 min [M−NHCOH] 409.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). At 0° C. to a solution of (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)formamide (72 mg, 0.16 mmol) in DCM (2 mL) was added triethylamine (0.06 mL, 0.43 mmol) and POCl3 (0.016 mL, 0.18 mmol). The reaction mixture was stirred at rt overnight, then diluted with EtOAc (15 mL). The organic layer was washed with sat. NaHCO3 and sat. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by ISCO chromatography (12 g) with 0-30% EtOAc in hexane to yield (R)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(1,1,2,2-tetrafluoroethoxy)benzene as a white solid (60 mg, 87% yield). LCMS: RT=2.10 min [M−NC] 409.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 3.56-3.65 (m, 2H), 5.74-6.01 (m, 1H), 6.84 (d, J=7.03 Hz, 2H), 6.94 (d, J=7.03 Hz, 3H), 7.04-7.10 (m, 2H), 7.16-7.26 (m, 3H), 7.32 (dd, J=9.01, 5.05 Hz, 2H).

1. washLCMS: RT=2.02 min [M−NHCOH] 409.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm)
2. washThe organic layer was washed with sat. NaHCO3 and sat. NaCl
3. dry with materialdried over Na2SO4
4. filtrationfiltered
5. concentrationconcentrated under reduced pressure
6. customThe crude product was purified by ISCO chromatography (12 g) with 0-30% EtOAc in hexane

ORD record

ord-2af11ba2b30c44bba666ca866f82946a

Source dataset

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08642576B2