Imidazole → (+/-)-(3R,4R)-benzyl 4-((tert-butyldimethylsilyl)oxy)-3-morpholinopiperidine-1-carboxylate

HRID 921678Notes

Reaction equation

HRID 921678 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.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.Cl([O-])(=O)(=O)=O.[Li+].N1C=CN=C1.[C:35]([Si:39]([CH3:42])([CH3:41])Cl)([CH3:38])([CH3:37])[CH3:36]>C(#N)C.ClCCl>[Si:39]([O:7][C@@H:6]1[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][C@H:1]1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:42])[CH3:41].[Si:39]([O:7][C@H:1]1[C@H:6]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[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)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:42])[CH3:41]

Participants

9

Reactant 5

HCID 795ImidazoleHCID 8083MorpholineHCID 28928tert-Butyldimethylsilyl chlorideHCID 13186888Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylateHCID 23665649Lithium perchlorate

Product 2

HCID 86708547(+/-)-(3R,4R)-benzyl 4-((tert-butyldimethylsilyl)oxy)-3-morpholinopiperidine-1-carboxylateHCID 86708548(+/-)-(3R,4R)-benzyl 3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (prepared according to a published literature procedure: Fink, Brian, et al., WO 2005/066176, 700 mg, 3.00 mmol), morpholine (0.581 mL, 6.00 mmol), and lithium perchlorate (639 mg, 6.00 mmol) in acetonitrile (10 mL) was heated at 80° C. for 4 h. Solvent was evaporated and the crude intermediate was dissolved in dichloromethane (10 mL), imidazole (654 mg, 9.60 mmol) and tert-butyldimethylchlorosilane (1357 mg, 9.00 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with dichloromethane and washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (220 g gold column, eluting with 5-30% ethyl acetate/hexanes) to give (+/−)-(3R,4R)-benzyl 4-((tert-butyldimethylsilyl)oxy)-3-morpholinopiperidine-1-carboxylate (Isomer A, 0.39 g) as a colorless oil and (+/−)-(3R,4R)-benzyl 3-((tert-butyldimethylsilyl)oxy)-4-morpholinopiperidine-1-carboxylate (Isomer B, 0.43 g) as a colorless oil. The structures were confirmed by NMR studies (1H-1D, 13C-1D, COSY, NOESY, dept-1H-13C-HSQC, 1H-13C-HMBC).

Workup

  1. customprepared
  2. customSolvent was evaporated
  3. dissolutionthe crude intermediate was dissolved in dichloromethane (10 mL)
  4. washwashed with water and brine
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product was purified by flash chromatography on silica gel using
  9. washan automated ISCO system (220 g gold column, eluting with 5-30% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-2a104a605ce34822b68da8f8bae057df
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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