Thionyl Chloride → (R)-4,4,4-trifluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,2-dimethylbutanamide

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Reaction Steps

To a solution of 4,4,4-trifluoro-2,2-dimethylbutanoic acid (30 mg, 0.176 mmol) in DCE (1 mL) was added SOCl2 (21 mg, 0.176 mmol) and the resulting mixture was refluxed for 2 h. After cooling to room temperature, TEA was added (82 uL, 0.59 mmol), followed by the addition 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, (25 mg, 0.059 mmol). The reaction mixture was heated to reflux overnight, concentrated and the residue was purified by preparative HPLC (Axia column, 30×100 mm, 40 mL/min, 40-100% ACN/H2O/0.1% TFA over 12 min) to give (R)-4,4,4-trifluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,2-dimethylbutanamide (Example 266) as a brownish oil (8 mg, 24% yield). LCMS: RT=2.13 min [M+H] 578.3 (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) ppm 1.28 (s, 6H), 2.21-2.51 (m, 2H), 3.77 (ABqt, J=13 Hz, 2H), 5.83 (t, J=53 Hz, 1H), 6.37 (s, 1H), 6.65-6.74 (m, 2H), 6.75-6.95 (m, 3H), 6.94-7.09 (m, 4H), 7.09-7.31 (m, 3H).

Provenance & Evidence