反应详情

To a solution of tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-fluoroethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (90 mg, 0.178 mmol) and sodium hydroxide (4N in water) (0.056 mL, 0.222 mmol) in ethanol (1.7 mL, 29.1 mmol) at 0 C was added NCS (47.5 mg, 0.356 mmol), it was stirred at 0 C for 2 h when most S.M. converted to product. The reaction was treated with 0.03 ml of 4 N NaOH, 1 eq. of NCS and was stirred at 0 C for another 2 h., there is still some unreacted SM by TLC. The reaction was quenched by addition of aqueous ammonia and diluted with Et2O. The organic layer was washed with water (2×) then brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (25% EtOAc/Hex) to give title compound (72 mg, 74.9% yield) as clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.57 (d, J=1.83, 1H), 7.28-7.25 (m, 2H), 7.09-7.06 (m, 3H), 4.6-4.4 (m, 3H), 3.77-3.6 (m, 2H), 3.51 (d, J=9.16 Hz, 1H), 3.39 (d, J=9.16 Hz, 1H), 3.08-2.95 (m, 2H), 2.27 (m, 1H), 2.05 (m, 1H), 1.86 (m, 1H), 1.74 (m, 1H), 1.43 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 161.8 (d, J=247.6 Hz), 154.9, 137.8, 137.6, 134.4, 128.73, 127.67, 126.7, 122.2, 121.8, 119.0, 115.9, 115.8, 85.7, 84.3, 81.1, 80.9, 79.7, 42.5, 41.4, 32.4, 32.1, 31.7, 28.5, 22.7, 14.2. LC/MS (HPLC method 3): tR=4.12 min, 540.1(MH)+.

1. stirringwas stirred at 0 C for another 2 h.
2. customThe reaction was quenched by addition of aqueous ammonia
3. additiondiluted with Et2O
4. washThe organic layer was washed with water (2×)
5. dry with materialbrine, dried over MgSO4
6. filtrationfiltered
7. concentrationconcentrated
8. customThe crude product was purified by silica gel column chromatography (25% EtOAc/Hex)