反应详情

To a solution of tert-butyl 4-cyano-4-isopropylpiperidine-1-carboxylate (90 mg, 0.357 mmol) in ammonium hydroxide (2 ml) and ethanol (4 ml) was added Raney nickel (100 mg, 1.167 mmol). The mixture was flushed with nitrogen, then flushed with hydrogen and stirred overnight under a hydrogen balloon, at which point LC/MS analysis showed the desired product. The mixture was filtered through a plug of Celite, washing liberally with methanol, and then concentrated to a small volume and partitioned between 20 ml of 1 N sodium hydroxide and 25 ml of ethyl acetate. The aqueous phase was extracted with 2×20 ml of ethyl acetate, and then the combined organics were washed with brine, dried (sodium sulfate), and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 50% methanol in dichloromethane over 10 column volumes to provide tert-butyl 4-(aminomethyl)-4-isopropylpiperidine-1-carboxylate (48 mg). The title compound was then prepared from tert-butyl 4-(aminomethyl)-4-isopropylpiperidine-1-carboxylate (48 mg) and 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (57 mg, INTERMEDIATE 2) as described in EXAMPLE 35. Mass spectrum (ESI) 545.3 (M+1). 1H NMR (500 MHz, CDCl3): 8.33 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.51 (s, 1H), 6.14 (br t, J=6.0 Hz, 1H), 3.63 (m, 4H), 3.47 (septet, J=7.0 Hz, 1H), 3.33 (br t, J=10.5 Hz, 2H), 1.83 (septet, J=7.0 Hz, 1H), 1.54-1.66 (m, 4H), 1.46 (d, J=7.0 Hz, 6H), 1.45 (s, 9H), 0.99 (d, J=7.0 Hz, 6H).

1. customThe mixture was flushed with nitrogen
2. customflushed with hydrogen
3. filtrationThe mixture was filtered through a plug of Celite
4. washwashing liberally with methanol
5. concentrationconcentrated to a small volume
6. custompartitioned between 20 ml of 1 N sodium hydroxide and 25 ml of ethyl acetate
7. extractionThe aqueous phase was extracted with 2×20 ml of ethyl acetate
8. washthe combined organics were washed with brine
9. dry with materialdried (sodium sulfate)
10. concentrationconcentrated
11. customThe residue was purified by flash chromatography on a Biotage Horizon, 25M column
12. washeluting with 1 column volume of 100% dichloromethane