Thionyl Chloride → N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)cyclobutanecarboxamide

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Reaction Steps

To a solution of 1-trifluoromethylcyclobutyl carboxylic acid (22.7 mg, 0.135 mmol) in DCE (1 mL) was added SOCl2 (16 mg, 0.135 mmol) and the resulting mixture was heated at reflux for 2 h. The reaction mixture was allowed to cool down to room temperature and TEA was added (31 μL, 0.23 mmol), followed by the addition of (S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine (20 mg, 0.045 mmol). The reaction was stirred at room temperature for 18 h, concentrated and the residue purified by preparative HPLC Shimadzu-AXIA column, 30×100 mm eluting with 30-100% MeOH (90% in H2O, 0.1% TFA) gradient over 12 min with flow rate 40 mL/min and UV detection at 220 nm to give N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)cyclobutanecarboxamide (5.2 mg, 22% yield). LCMS: RT=2.14 min [M+H] 525.2 (LCMS Method 2.); NMR: 400 MHz 1H (CDCl3) 8.29 ppm, 1H, s; 8.13 ppm, 1H, s; 7.68 ppm, 1H, m; 7.11 ppm, 6H, m; 6.87 ppm, 1H, m; 6.57 ppm, 2H, m; 5.87 ppm, 1H, t, J=53 Hz; 4.45 ppm, 1H, dd, J=12.8, 3.6 Hz; 3.51 ppm, 1H, dd, J=12.8, 3.6 Hz; 3.09 ppm, 1H, m; 2.20 ppm, 4H, m; 1.94 ppm, 2H, m.

Provenance & Evidence