Ethyl Acetate → (+)-6-fluoro-5-methoxy-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol

Participants

Reaction Conditions

Reaction Steps

1.32 g (3.117 mmol) of the above-described imine, 1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol, is dissolved in 22.8 ml of dichloromethane. 9.35 ml of a 1 M solution of TiCl4 in dichloromethane (3 equivalents) is added to this solution at −30° C., specifically under nitrogen within 15 minutes. The reaction mixture is stirred for three and one-half hours at −30 to −15° C. The batch is mixed drop by drop with saturated sodium bicarbonate solution at −30° C. After dilution with ethyl acetate, it is stirred for 15 minutes at room temperature. After 2× extraction with 150 ml each of ethyl acetate, the organic phases are washed (water, brine), dried (Na2SO4), and the solvent is spun off. After chromatography on silica gel (mobile solvent dichloromethane/methanol), 1.07 g (81.1%) of the desired product is obtained as a racemate. The product is separated into its enantiomers (Chiralpak AD 5μ; mobile solvent hexane/ethanol). The (+)-enantiomer shows an angle of rotation of [α]D=+1.6° (c=1, MeOH), and the (−)-enantiomer shows an angle of rotation of [α]D=−1.3° (c=1, MeOH).

Provenance & Evidence