4-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine-1-carbonitrile → 5-(4-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole

HRID 1850775Notes

Reaction equation

HRID 1850775 reaction equation
[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:22]#[N:23])[CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[OH:26][NH:27][C:28](=N)[CH:29]([CH3:31])[CH3:30]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:17][CH2:18][N:19]([C:22]4[O:26][N:27]=[C:28]([CH:29]([CH3:31])[CH3:30])[N:23]=4)[CH2:20][CH2:21]3)=[CH:24][CH:25]=2)[CH:5]=[N:4][N:3]=[N:2]1

Participants

5

Reactant 2

HCID 867112014-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine-1-carbonitrileHCID 178449908HCID 178449908, compound

Product 1

HCID 708559775-(4-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazoleYield 38.3%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 4-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine-1-carbonitrile (Step A, Example 83; 150 mg, 0.444 mmol) and N-hydroxyisobutyrimidamide (54 mg, 0.53 mmol) in tetrahydrofuran (5 mL) was added zinc chloride (1.1 mL, 0.5 M in tetrahydrofuran, 0.53 mmol). The mixture was refluxed for 2 h, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in 2 mL of 4N HCl ethanol and water (1:1). The solution was refluxed for 1 hour, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (5 mL), neutralized by the addition of excess potassium carbonate, mixed with silica gel (2 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (15 g of silica gel) and eluted with dichloromethane/methanol (199:1, 1 L) to provide impure product (72 mg).

Workup

  1. temperatureThe mixture was refluxed for 2 h
  2. concentrationconcentrated to dryness under reduced pressure
  3. dissolutionThe residue was dissolved in 2 mL of 4N HCl ethanol
  4. temperatureThe solution was refluxed for 1 hour
  5. temperaturecooled to RT
  6. concentrationconcentrated to dryness under reduced pressure
  7. dissolutionThe residue was dissolved in methanol (5 mL)
  8. additionneutralized by the addition of excess potassium carbonate
  9. additionmixed with silica gel (2 g)
  10. concentrationconcentrated to dryness under reduced pressure
  11. washeluted with dichloromethane/methanol (199:1, 1 L)

Sources & evidence

ORD record
ord-a169b2abb57b47e2a665fb5f09caa92d
Source dataset
uspto-grants-2015_02
Patent number
US08957062B2

Reaction notes

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