反应详情

Prepared as described for Example 1, using 2,4-dichloro-beta-nitrostyrene in Step 2 with heating at 200° C. in a microwave apparatus; m/z (ES−) 522 (M−H+). The enantiomers and diastereomers could be separated by supercritical fluid chromatography. A CHIRALPAK AD-H column 250×10 mm (5μ) Column temperature 40° C., Mobile phase: 85/15 CO2/MeOH, Flow rate: 10 mL/min, outlet pressure 100 bar gave pure Example 2a ((7S)-3-(2,4-dichlorophenyl)-1-{(1S)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid eluting at 5.50 min 1H NMR δ (ppm) (CDCl3): 7.55 (2 H, d, J=8.2 Hz), 7.46 (1 H, d, J=2.0 Hz), 7.29 (1 H, s), 7.22 (1 H, dd, J=2.1, 8.3 Hz), 7.14 (2 H, d, J=8.1 Hz), 7.04 (1 H, s), 5.14 (1 H, dd, J=6.3, 9.0 Hz), 3.04 (1 H, s), 2.66 (2 H, d, J=6.7 Hz), 2.42 (2 H, t, J=3.7 Hz), 2.24-2.16 (1 H, m), 2.11-2.04 (1 H, m), 1.81-1.66 (5 H, m), 1.42 (1 H, dd, J=0.0, 6.6 Hz), 1.21 (3 H, d, J=6.1 Hz), 1.01 (3 H, t, J=7.3 Hz), a mixture of Example 2b ((7S)-3-(2,4-dichlorophenyl)-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid and Example 2c ((7R)-3-(2,4-dichlorophenyl)-1-{(1S-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid eluting at 6.25 min and finally pure Example 2d ((7R)-3-(2,4-dichlorophenyl)-1-{(1R)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid eluting at 7.35 min 1H NMR δ (ppm) (CDCl3): 7.55 (2 H, d, J=8.2 Hz), 7.46 (1 H, d, J=2.0 Hz), 7.29 (1 H, s), 7.22 (1 H, dd, J=2.1, 8.3 Hz), 7.14 (2 H, d, J=8.1 Hz), 7.04 (1 H, s), 5.14 (1 H, dd, J=6.3, 9.0 Hz), 3.04 (1 H, s), 2.66 (2H, d, J=6.7 Hz), 2.42 (2 H, t, J=3.7 Hz), 2.24-2.16 (1 H, m), 2.11-2.04 (1 H, m), 1.81-1.66 (5 H, m), 1.42 (1 H, dd, J=0.0, 6.6 Hz), 1.21 (3 H, d, J=6.1 Hz), 1.01 (3 H, t, J=7.3 Hz). The mixture of Example 2b and Example 2c were separated by further SFC purification using a CHIRALCEL OJ-H column 250×10 mm (5μ) Column temperature 40° C., Mobile phase: 80/20 CO2/MeOH, Flow rate: 10 mL/min, outlet pressure 100 bar gave Example 2b ((7R)-3-(2,4-dichlorophenyl)-1-{(1S)-1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid eluting at 3.04 min 1H NMR δ (ppm)(CDCl3): 7.59 (2 H, d, J=8.1 Hz), 7.46 (1 H, d, J=1.8 Hz), 7.32 (2 H, d, J=8.1 Hz), 7.30 (1 H, d, J=8.3 Hz), 7.22 (1 H, dd, J=8.3, 1.8 Hz), 6.96 (1 H, s), 5.18 (1 H, t, J=7.6 Hz), 3.38 (1 H, d, J=8.5 Hz), 2.48-2.43 (2 H, m), 2.29 (1 H, dd, J=11.0, 15.6 Hz), 2.12-2.06 (2 H, m), 2.03 (1 H, d, J=15.6 Hz), 1.88-1.76 (3 H, m), 1.68 (1 H, m), 1.38-1.30 (2 H, m), 0.96 (3 H, t, J=7.3 Hz) and Example 2c ((7S)-3-(2,4-dichlorophenyl)-1-{(1R)-1-[4-(trifluoromethyl)phenyl] butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid eluting at 4.13 min 1H NMR δ (ppm)(CDCl3): 7.59 (2 H, d, J=8.1 Hz), 7.46 (1 H, d, J=1.8 Hz), 7.32 (2 H, d, J=8.1 Hz), 7.30 (1 H, d, J=8.3 Hz), 7.22 (1 H, dd, J=8.3, 1.8 Hz), 6.96 (1 H, s), 5.18 (1 H, t, J=7.6 Hz), 3.38 (1 H, d, J=8.5 Hz), 2.48-2.43 (2 H, m), 2.29 (1 H, dd, J=11.0, 15.6 Hz), 2.12-2.06 (2 H, m), 2.03 (1 H, d, J=15.6 Hz), 1.88-1.76 (3 H, m), 1.68 (1 H, m), 1.38-1.30 (2 H, m), 0.96 (3 H, t, J=7.3 Hz).

1. customThe mixture of Example 2b and Example 2c were separated by further SFC purification
2. customa CHIRALCEL OJ-H column 250×10 mm (5μ) Column temperature 40° C., Mobile phase