反应详情

(±)-tert-Butyl 4-((1-(5-fluoro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (200 mg, 0.332 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 6 mL) and stirred at room temperature for 4 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 92.5 mg of (±)-5-fluoro-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-2H-indazole (74.9%). The crude amine (92.5 mg, 0.249 mmol) in dichloromethane (2.5 mL) was cooled to 0° C. and treated with di-tert-butyl dicarbonate (109 mg, 0.498 mmol). The reaction was stirred at 0° C. for 1 h and was quenched by addition of 2 M ammonia in methanol and concentrated. The residue was purified by column chromatography (15%→30% EtOAc/Hex) to give 108 mg (92%) as white foam. 1H-NMR (CDCl3, 300 MHz) δ 9.68(bs, 1H), 7.90(s, 1H), 7.17-7.28(m, 3H), 7.01-7.10(m, 2H), 6.80(m, 1H), 4.48(q, J=6.0 Hz, 1H), 3.60-3.80(m, 2H), 3.36 (d, J=9 Hz, 1H), 3.25 (d, J=9 Hz, 1H), 2.90-3.10(m, 2H), 2.01-2.25(m, 2H), 1.68-1.87(m, 2H), 1.39-1.41(m, 12H); 13C-NMR (CDCl3, 76MHz) δ 161.5 (d, J=981 Hz), 157.4 (d, J=948 Hz), 154.8, 137.9, 134.2, 133.8, 128.6, 127.4, 123.7, 115.7, 115.4, 113.2, 112.9, 103.7, 103.4, 79.4, 78.5, 78.2, 60.27, 41.0, 32.3, 32.0, 28.33, 22.0; Mass spec.: 472.51 (MH)+.

1. concentrationThe reaction was concentrated
2. customThe cartridge was flushed with several volumes of methanol which
3. washThe product was eluted with 2 M ammonia in methanol
4. concentrationconcentrated