Hydroxyamine hydrochloride → tert-butyl (3S,5R)-3-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino]-5-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate

HRID 1184148Notes

Reaction equation

HRID 1184148 reaction equation
Cl.[NH2:2]O.[C:4](=[O:7])([O-])O.[Na+].[C:9]([C@@H:11]1[CH2:16][C@H:15]([N:17]([C:22]([C:24]2[N:28]([CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:27]3[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=3[N:25]=2)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][N:13]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:12]1)#[N:10]>CS(C)=O.O>[CH3:34][O:33][CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:27]2[CH:35]=[CH:36][CH:37]=[CH:38][C:26]=2[N:25]=[C:24]1[C:22]([N:17]([CH2:18][CH:19]([CH3:20])[CH3:21])[C@H:15]1[CH2:16][C@@H:11]([C:9]2[N:2]=[CH:4][O:7][N:10]=2)[CH2:12][N:13]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:14]1)=[O:23]

Participants

6

Reactant 3

HCID 443297Hydroxyamine hydrochlorideHCID 516892Sodium BicarbonateHCID 58355698tert-butyl (3R,5S)-3-cyano-5-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate

Product 1

HCID 58355386tert-butyl (3S,5R)-3-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino]-5-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxylateYield 75.2%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolvent2×HCID 962WaterSolvent

Conditions

Temperature
40 °C

Procedure

Hydroxylamine hydrochloride (383 mg) was dissolved in dimethyl sulfoxide (10 ml), and the mixture was stirred at 40° C. for 30 min. Sodium hydrogen carbonate (463 mg) was added, and the mixture was stirred at 50° C. for 1 hr. A solution of tert-butyl (3R,5S)-3-cyano-5-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate (282 mg) in dimethyl sulfoxide (10 ml) was further added, and the mixture was stirred at 90° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, diluted with water, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in trimethyl orthoformate (5 ml) and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-3:7) was concentrated under reduced pressure to give the object product (230 mg).

Workup

  1. stirringthe mixture was stirred at 50° C. for 1 hr
  2. stirringthe mixture was stirred at 90° C. for 3 hr
  3. temperatureto cool to room temperature
  4. extractionextracted with ethyl acetate
  5. dry with materialThe extract was dried over anhydrous magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. dissolutionThe residue was dissolved in trimethyl orthoformate (5 ml)
  8. stirringthe mixture was stirred at 100° C. for 4 hr
  9. concentrationThe reaction mixture was concentrated under reduced pressure
  10. washa fraction eluted with ethyl acetate-hexane (5:95-3:7)
  11. concentrationwas concentrated under reduced pressure

Sources & evidence

ORD record
ord-045d0fb1fceb45bbb5048d91fb1536cc
Source dataset
uspto-grants-2014_03
Patent number
US08664380B2

Reaction notes

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