Sodium Carbonate → 2-(3-{[(Benzyloxy)carbonyl]amino}oxetan-3-yl)acetic acid

HRID 1523295Notes

Reaction equation

HRID 1523295 reaction equation
C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1([CH2:12][C:13]([O:15]CC)=[O:14])[CH2:11][O:10][CH2:9]1.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CCCCCCC.C(OCC)(=O)C.COC(C)(C)C.O>[CH2:22]([O:21][C:19]([NH:7][C:8]1([CH2:12][C:13]([OH:15])=[O:14])[CH2:9][O:10][CH2:11]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1

Participants

8

Reactant 3

HCID 10340Sodium CarbonateHCID 10387Benzyl chloroformateHCID 55280628Ethyl 2-(3-aminooxetan-3-yl)acetate

Product 1

HCID 895254372-(3-{[(Benzyloxy)carbonyl]amino}oxetan-3-yl)acetic acidYield 73.3%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 8900HeptaneSolventHCID 15413tert-Butyl methyl etherSolvent3×

Conditions

Temperature
5 °C

Procedure

tert-Butyl methyl ether (2.5 L) and an aqueous solution of sodium carbonate (750 g in 2.2 L water, 7.07 mol) were stirred. Ethyl (3-aminooxetan-3-yl)acetate (Preparation 30, 875 g, 5.5 mol) was added to the reaction followed by further tert-butyl methyl ether (2.5 L). The reaction was cooled to 5° C. and benzyl chloroformate (1.21 Kg, 7.09 mol) added in a controlled manner such as to maintain the temperature below 20° C. A precipitate was observed so further water (5 L) and tert-butyl methyl ether (1.5 L) were added to solubilise the reaction mixture. The biphasic mixture was separated. The organic layer was basified with 2M aqueous solution of sodium hydroxide (3.5 L) and stirred vigorously for 18 hours. The aqueous layer was separated and the remaining organic layer washed with water (1.5 L). The aqueous layers were combined and cooled to 15° C. Isopropyl acetate (5 L) was added followed by controlled addition of a 6M aqueous solution of hydrogen chloride (1.2 L), maintaining the temperature below 17° C. The reaction was stirred for 30 minutes. Solid crystallised out in the reactor so was dissolved in a mixture of ethyl acetate and methanol (˜20 L). The solution was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo to afford solid material. Ethyl acetate (5 L) was added and concentrated in vacuo. Further ethyl acetate (5 L) was added and the slurry heated to reflux to give an orange solution. The solution was cooled to 50° C. and heptane (2.5 L) added. A thick slurry was observed that was stirred at room temperature for 18 hours. The solid was filtered and dried on a sinter for 3 hours before drying in vacuo at 40° C. for 18 hours to afford the title compound as a white crystalline solid (1.07 Kg, 73% yield).

Workup

  1. temperatureto maintain the temperature below 20° C
  2. additionwere added
  3. customThe biphasic mixture was separated
  4. customThe aqueous layer was separated
  5. washthe remaining organic layer washed with water (1.5 L)
  6. temperaturecooled to 15° C
  7. additionIsopropyl acetate (5 L) was added
  8. additionfollowed by controlled addition of a 6M aqueous solution of hydrogen chloride (1.2 L)
  9. temperaturemaintaining the temperature below 17° C
  10. stirringThe reaction was stirred for 30 minutes
  11. customSolid crystallised out in the reactor
  12. dissolutionso was dissolved in a mixture of ethyl acetate and methanol (˜20 L)
  13. stirringThe solution was stirred at room temperature for 18 hours
  14. concentrationThe reaction was concentrated in vacuo
  15. customto afford solid material
  16. concentrationconcentrated in vacuo
  17. additionFurther ethyl acetate (5 L) was added
  18. temperaturethe slurry heated
  19. temperatureto reflux
  20. customto give an orange solution
  21. temperatureThe solution was cooled to 50° C.
  22. stirringthat was stirred at room temperature for 18 hours
  23. filtrationThe solid was filtered
  24. customdried on a sinter for 3 hours
  25. custombefore drying in vacuo at 40° C. for 18 hours

Sources & evidence

ORD record
ord-84a1edc8f8434d0cbcec3b874b66dc88
Source dataset
uspto-grants-2015_07
Patent number
US09079878B2

Reaction notes

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