Reaction Steps
(3R)-tert-butyl 4-(2-(2-chloro-3-cyano-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (15.6 g, 37.3 mmol) and cyanomethylene tri-n-butyl phosphorane (16.4 g, 67.8 mmol) were dissolved in benzene (90 mL), degassed and heated at 100° C. for 16 h. The reaction mixture was concentrated and chromatographed through a 330 g ISCO Redi-sep column and eluted with 35% EtOAc/hexane to yield the title compound (cis-trans diastereomers mixture). LC-MS (IE, m/z): 396 [M+1]+; The cis-trans diastereomers were separated by SFC-HPLC using the following condition: Chiralpak AD 21×250 mm, 20% IPA, 50 ml/min, ˜85 mg/mL in 1:1 MeOH/MeCN, 100 bar, 220 nm, 35° C. 31A: 1H-NMR (600 MHz, CDCl3) δ ppm 7.826 (dd, J=8.7, 6.5 Hz, 1H), 7.184 (t, J=8.4 Hz, 1H), 4.975 (dd, J=9.6, 1.9 Hz, 1H), 3.989 (b, 2H), 3.953 (dd, J=5.7, 3.2 Hz, 1H) 3.484 (t, J=10.85 Hz, 1H), 3.015 (dd, J=11.4, 2.2 Hz, 2H), 2.733 (d, J=10.3 Hz, 1H), 2.52 (b, 1H), 2.18-2.26 (m, 2H), 1.981 (t, J=10.85 Hz, 1H), 1.474 (s, 9H). 31B: 1H-NMR (600 MHz, CDCl3) δ ppm 8.331 (s, 1H), 7.163 (t, J=8.35 Hz, 1H), 5.038 (t, J=3.7 Hz, 1H), 3.738-3.947 (b, 2H), 3.649 (d, J=10.9 Hz, 1H) 3.371 (s, 1H), 3.02 (dd, J=12, 4.1 Hz, 2H), 2.843 (dd, J=12, 3.8 Hz, 1H), 2.784 (d, J=9.4 Hz, 2H), 2.556 (b, 2H), 1.471 (s, 9H).
