Imidazole → HCID 86708513, compound

HRID 921657Notes

Reaction equation

HRID 921657 reaction equation
[CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.CN.C(N(CC)CC)C.[C:27](O[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[NH:42]1[CH:46]=[CH:45][N:44]=[CH:43]1.[C:47]([Si:51]([CH3:54])([CH3:53])Cl)([CH3:50])([CH3:49])[CH3:48]>C(O)C.CN(C=O)C.O>[C:38]([O:37][C:35]([N:42]([CH3:46])[C@H:1]1[C@H:6]([O:7][Si:51]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:54])[CH3:53])[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]1)=[O:36])([CH3:39])([CH3:40])[CH3:41].[C:30]([O:29][C:27]([N:44]([CH3:43])[C@@H:45]1[CH2:46][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:2][C@H:1]1[O:7][Si:51]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:54])[CH3:53])=[O:28])([CH3:33])([CH3:32])[CH3:31]

Participants

11

Reactant 6

HCID 795ImidazoleHCID 6329MethylamineHCID 8471TriethylamineHCID 28928tert-Butyldimethylsilyl chlorideHCID 90495Di-tert-butyl dicarbonateHCID 13186888Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate

Product 2

HCID 86708513HCID 86708513, compoundHCID 86708514HCID 86708514, compound

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (0.7 g, 3.00 mmol) and methanamine (3.75 mL, 30.0 mmol) in ethanol (5 mL) was heated in a sealed reaction pressure vessel at 70° C. overnight. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in dichloromethane (5.00 mL), triethylamine (0.502 mL, 3.60 mmol) and di-tert-butyl dicarbonate (0.766 mL, 3.30 mmol) were added and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water and brine, dried over magnesium sulfate and concentrated to give colorless oil. The above oil was dissolved in DMF (5.00 mL), imidazole (0.409 g, 6.00 mmol) and tert-butyldimethylchlorosilane (0.678 g, 4.50 mmol) was added. The mixture was stirred at room temperature overnight. Water was added and the reaction mixture was extracted with ethyl acetate (3×), the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (80 g gold column, eluting with 5-30% ethyl acetate/hexanes) to give (+/−)-(3R,4R)-benzyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (Isomer A, 0.697 g) and (+/−)-(3R,4R)-benzyl 4-((tert-butoxycarbonyl)(methyl)amino)-3-((tert-butyldimethylsilyl)oxy)piperidine-1-carboxylate (Isomer B, 0.556 g). The structures were confirmed by NMR studies (1H-1D, 13C-1D, COSY, NOESY, dept-1H-13C-HSQC, 1H-13C-HMBC).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. concentrationconcentrated to dryness
  3. dissolutionThe residue was dissolved in dichloromethane (5.00 mL)
  4. washThe reaction mixture was washed with water and brine
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated
  7. customto give colorless oil
  8. stirringThe mixture was stirred at room temperature overnight
  9. extractionthe reaction mixture was extracted with ethyl acetate (3×)
  10. dry with materialthe organic layer was dried over magnesium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customthe crude product was purified by flash chromatography on silica gel using
  14. washan automated ISCO system (80 g gold column, eluting with 5-30% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-aa200e4bda9241cea4efaaeb0cfa4ad7
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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