(2S)-2-(Trifluoromethyl)oxirane → (R)-3-((S)-1-(5-chloropyridin-2-yl)-1-(3fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylamino)-1,1,1-trifluoropropan-2-ol

Participants

Reaction Conditions

Reaction Steps

(S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl ethanamine (0.148 g, 0.376 mmol, prepared as described in Procedures 5, 6 and 7) was dissolved in anhydrous acetonitrile (1 mL). (S)-2-(trifluoromethyl)oxirane (approximate 85:15 ratio of R to S) (0.20 mL, excess) was added to the solution in a microwave vial followed by Yb(OSO2CF3)3 (0.020 g, mmol). The sealed vial was heated to 140° C. for 20 mins in the microwave. The reaction mixture was taken from the reaction vial via syringe and injected directly onto a silica gel ISCO cartridge column (40 g). The product eluted at 8 minutes with a gradient of 0-50% EtOAc in hexanes over 18 minutes and flow rate of 40 mL/min, (0.122 mg, 64% yield). The crude NMR of this material showed an 85:15 ratio of R to S at the hydroxy centre. The material was further purified on a Chiral cell AD column with 5% IPA in hexane as the mobile phase yielding 0.068 g of (R)-3-((S)-1-(5-chloropyridin-2-yl)-1-(3fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylamino)-1,1,1-trifluoropropan-2-ol as a colorless oil and a further 0.044 g of mixed fractions. LCMS: 2.06 min [M+1] 507.2 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 7.88 min (8 min gradient, MeOH/H2O 0.2% PPA Purity 100%; NMR: 400 MHz 1H (CDCl3) 8.42 ppm, 1H, d, J=2.2 Hz; 7.55 ppm, 1H, dd, J=8.36 and J=2.64 Hz; 7.30 ppm, 1H, s; 7.13 ppm, 3H, m; 7.08 ppm, 2H, m; 6.57 ppm, 2H, d, J=7.04 Hz; 3.85 ppm, IH, m; 3.76 ppm, 1H, d, J=12.2 Hz; 3.50 ppm, 1H, d, J=12.2 Hz; 2.78 ppm, 1H, dd, J=6.12 and 12.0 Hz; 2.64 ppm, 1H, dd, J=3.96 and J=12.2 Hz.

Provenance & Evidence