[F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:18][C@H:19]([CH3:22])[CH2:20][OH:21].C(N(CC)CC)C>C(O)C.ClCCl>[CH3:18][C@@H:19]([CH2:22][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)[CH2:20][OH:21]A solution of 1-(4-trifluoromethyl-phenyl)-piperazine (52.0 g; 221 mmol); (R)-3-bromo-2-methyl-propan-1-ol (36.0 g; 226 mmol) and triethylamine (61.7 mL; 443 mmol) in ethanol (350 mL) is heated at 95° C. for 45 hours. After cooling to room temperature, the mixture is concentrated under reduced pressure. The residue obtained is diluted with dichloromethane (500 mL) and the organic layer is washed with water (500 mL); with brine (500 mL) and the solvent is removed under reduced pressure. The crude residue obtained is re-crystallized from ethanol (200 mL), the re-crystallized product is washed with cold ethanol (100 mL). The mother liquor is concentrated under reduced pressure and is crystallized from ethanol (100 mL). The precipitate obtained is washed with cold ethanol (50 mL). The combined fractions are dried overnight at 40° C. under 3 mbar to deliver the enantiopure product (53.7 g; 178 mmol).
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