Pyridine → 1-[4-[5-[5-Amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-1-methyl-1,2,4-triazol-3-yl]-1-piperidyl]-2-hydroxy-2-methyl-propan-1-one

HRID 1749690Notes

Reaction equation

Cl.CN(C)CCCN=C=NCC.[OH:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16].[C:20]([C:24]1[O:28][C:27]([C:29]2[C:30]([NH2:47])=[N:31][CH:32]=[C:33]([C:35]3[N:39]([CH3:40])[N:38]=[C:37]([CH:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)[N:36]=3)[N:34]=2)=[N:26][N:25]=1)([CH3:23])([CH3:22])[CH3:21].OC1C=CC=C[N+]=1[O-].N1C=CC=CC=1>CN1C(=O)CCC1>[NH2:47][C:30]1[N:31]=[CH:32][C:33]([C:35]2[N:39]([CH3:40])[N:38]=[C:37]([CH:41]3[CH2:46][CH2:45][N:44]([C:15](=[O:16])[C:14]([OH:13])([CH3:19])[CH3:18])[CH2:43][CH2:42]3)[N:36]=2)=[N:34][C:29]=1[C:27]1[O:28][C:24]([C:20]([CH3:23])([CH3:21])[CH3:22])=[N:25][N:26]=1

Participants

Conditions

Temperature: 25 °C

Procedure

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) was added in one portion to 2-hydroxy-2-methylpropanoic acid (38.0 mg, 0.37 mmol), 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (100 mg, 0.26 mmol) and 2-hydroxy-pyridine N-oxide (57.9 mg, 0.52 mmol) dissolved in NMP (1.2 mL) under argon. The resulting solution was stirred at 25° C. for 3 hours. Pyridine (100 μL, 1.24 mmol) was added and the mixture was stirred for 18 hours. Additional 2-hydroxypyridine 1-oxide (57.9 mg, 0.52 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) was added. The mixture was then heated up to 70° C. for 48 hours, more 2-hydroxy-2-methylpropanoic acid (15 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 2-hydroxypyridine 1-oxide (25.0 mg, 0.23 mmol) were added and the mixture was then kept to 70° C. for 8 hours. The solution was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent to afford the title compound (71 mg, 58%) as a pale yellow solid. 1H NMR Spectrum: (CDCl3) 1.55 (15H, s br), 1.90 (2H, m), 2.15 (2H, m), 3.05-3.3 (4H, m), 4.32 (3H, s), 4.6 (1H, m), 9.03 (1H, s); Mass Spectrum [M+H]+=470.

Workup

stirringthe mixture was stirred for 18 hours
temperatureThe mixture was then heated up to 70° C. for 48 hours
waitthe mixture was then kept to 70° C. for 8 hours
customThe solution was purified by preparative HPLC

Sources & evidence

ORD record: ord-65c8f2e58c8c4b048587a36ab518745e
Source dataset: uspto-grants-2015_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09156831B2

Reaction notes

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