4-(5-Cyano-7-isopropylbenzo[d]oxazol-2-yl)benzoic acid → tert-Butyl 4-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)-4-isopropylpiperidine-1-carboxylate
Reaction equation
[NH2:1][CH2:2][C:3]1([CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[C:19]([C:21]1[CH:22]=[C:23]([CH:39]([CH3:41])[CH3:40])[C:24]2[O:28][C:27]([C:29]3[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH:38]=1)#[N:20]>>[C:19]([C:21]1[CH:22]=[C:23]([CH:39]([CH3:41])[CH3:40])[C:24]2[O:28][C:27]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([NH:1][CH2:2][C:3]4([CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5][CH2:4]4)=[O:34])=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH:38]=1)#[N:20]Participants
Procedure
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).
Sources & evidence
- ORD record
- ord-988acbcd1baf42febabae954b02d695b
- Source dataset
- uspto-grants-2013_05
- Patent number
- US08445480B2
Reaction notes
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