Acetonitrile → (2S,5R)-methyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate

HRID 710963Notes

Reaction equation

HRID 710963 reaction equation
[CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][NH:14][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[O:23]=[C:24](Cl)OC(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:1]([O:8][N:9]1[C:24](=[O:23])[N:14]2[CH2:15][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 3

HCID 6342AcetonitrileHCID 10426DiphosgeneHCID 71722743methyl (2S,5R)-5-(phenylmethoxyamino)piperidine-2-carboxylate

Product 1

HCID 57389436(2S,5R)-methyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylateYield 71%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8471TriethylamineSolvent

Conditions

Temperature
2 °C

Procedure

To (2S,5R)-methyl 5-(benzyloxyamino)piperidine-2-carboxylate (1.154 g, 4.37 mmol) was added dehydrated acetonitrile (198 mL), followed by ice-cooling. Triethylamine (1.60 mL) and diphosgene (0.389 mL) were sequentially added dropwise at 5° C. or less, followed by stirring at 2° C. for 20 minutes. Then, to the reaction solution was added 4-dimethylaminopyridine (70.0 mg), followed by stirring at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure, followed by substituting and concentrating with ethyl acetate three times, and the solution was concentrated to 30 mL. Ethyl acetate (20 mL) and water (40 mL) were added thereto, followed by liquid separation, and the separated aqueous layer was extracted with ethyl acetate (30 mL) twice. The combined organic layers were washed with 5% citric acid aqueous solution (40 mL), 6.5% sodium bicarbonate aqueous solution (30 mL), and 5% brine (30 mL), and dried over anhydrous sodium sulfate, followed by filtration and concentration under reduced pressure. 1.16 g of the resulting residue was diluted with ethyl acetate (5.5 mL), and n-hexane (11 mL) was added, and a seed crystal was inoculated for crystallization. Further, n-hexane (49 mL) was added, followed by stirring at 0° C. for 1 hour. Subsequently, crystals were filtered, washed with n-hexane (60 mL), and then dried under vacuum to afford 882.3 mg of the title compound as colorless crystalline powder (yield 71%).

Workup

  1. temperaturecooling
  2. stirringby stirring at room temperature for 10 hours
  3. concentrationThe reaction solution was concentrated under reduced pressure
  4. concentrationconcentrating with ethyl acetate three times
  5. concentrationthe solution was concentrated to 30 mL
  6. additionEthyl acetate (20 mL) and water (40 mL) were added
  7. customfollowed by liquid separation
  8. extractionthe separated aqueous layer was extracted with ethyl acetate (30 mL) twice
  9. washThe combined organic layers were washed with 5% citric acid aqueous solution (40 mL), 6.5% sodium bicarbonate aqueous solution (30 mL), and 5% brine (30 mL)
  10. dry with materialdried over anhydrous sodium sulfate
  11. filtrationfollowed by filtration and concentration under reduced pressure
  12. addition1.16 g of the resulting residue was diluted with ethyl acetate (5.5 mL), and n-hexane (11 mL)
  13. additionwas added
  14. customa seed crystal was inoculated for crystallization
  15. additionFurther, n-hexane (49 mL) was added
  16. stirringby stirring at 0° C. for 1 hour
  17. filtrationSubsequently, crystals were filtered
  18. washwashed with n-hexane (60 mL)
  19. customdried under vacuum

Sources & evidence

ORD record
ord-2d9bef4d8af04c5fad4ddc672663bd61
Source dataset
uspto-grants-2015_11
Patent number
US09181250B2

Reaction notes

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