4-Methylmorpholine → Tert-butyl 4-{3-[4-(methylthio)benzyl]-1,2,4-oxadiazol-5-yl}piperidine-1-carboxylate

HRID 1434596Notes

Reaction equation

HRID 1434596 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=N.O[N:45]=[C:46]([NH2:56])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([S:54][CH3:55])=[CH:50][CH:49]=1>ClCCl.O1CCOCC1>[CH3:55][S:54][C:51]1[CH:50]=[CH:49][C:48]([CH2:47][C:46]2[N:45]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)[O:16][N:56]=2)=[CH:53][CH:52]=1

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 757711-HydroxybenzotriazoleHCID 3928711-(tert-Butoxycarbonyl)-4-piperidinecarboxylic acidHCID 5152844N'-hydroxy-2-[4-(methylthio)phenyl]ethanimidamideHCID 21899179Dimethylaminopropyl carbodiimide hydrochloride

Product 1

HCID 68710908Tert-butyl 4-{3-[4-(methylthio)benzyl]-1,2,4-oxadiazol-5-yl}piperidine-1-carboxylateYield 54.2%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Procedure

1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (1.00 g, 4.36 mmol), 1-hydroxybenzotriazole (589 mg, 4.36 mmol) and N-methylmorpholine(0.97 mL, 8.72 mmol) were dissolved in dicloromethane (50 mL), under argon, and (3-dimethylaminopropyl)carbodiimide hydrochloride (921 mg, 8.72 mmol) and N′-hydroxy-2-[4-(methylthio)phenyl]ethanimidamide (855 mg, 4.36 mmol) were added. The mixture was stirred at room temperature for 92 hours. The organics were washed with sodium hydroxide (0.1 N) and citric acid (0.5M), dried (phase separating filter) and the solvent evaporated to give a yellow oil which was redissolved in 1,4-dioxane (100 mL) and heated to reflux for 5 hours, cooled and the solvent evaporated and chromatographed (50 g Silica Isolute, eluent 20% ethyl acetate/isohexane) to give a yellow oil, tert-butyl 4-{3-[4-(methylthio)benzyl]-1,2,4-oxadiazol-5-yl}piperidine-1-carboxylate (920 mg, 54%); NMR (CDCl3): 1.46 (9H, s), 1.71-1.87 (2H, m), 2.03 (2H, m), 2.48 (3H, m), 2.92 (2H, t), 3.05 (1H, m), 4.00 (2H, s), 4.07 (2H, m), 7.24 (4H, m).

Workup

  1. washThe organics were washed with sodium hydroxide (0.1 N) and citric acid (0.5M)
  2. customdried
  3. custom(phase separating filter)
  4. customthe solvent evaporated
  5. customto give a yellow oil which
  6. temperatureheated
  7. temperatureto reflux for 5 hours
  8. temperaturecooled
  9. customthe solvent evaporated
  10. customchromatographed (50 g Silica Isolute, eluent 20% ethyl acetate/isohexane)

Sources & evidence

ORD record
ord-88601cc49749404cb4f9368141168a39
Source dataset
uspto-grants-2009_11
Patent number
US07615555B2

Reaction notes

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