Phosgene → (3S-trans)-N-[[3-[[t-Butoxycarbonyl]amino]-4-methyl-2-oxo-1-azetidinyl]carbonyl]-N-methylglycine, t-butyl ester

HRID 482926Notes

Reaction equation

HRID 482926 reaction equation
[C:1](Cl)(Cl)=[O:2].[CH3:5][NH:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(N(CC)CC)C.[C:22]([O:26][C:27]([NH:29][C@H:30]1[C@H:33]([CH3:34])[NH:32][C:31]1=[O:35])=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.ClCCl.C(OCC)(=O)C>[C:22]([O:26][C:27]([NH:29][C@H:30]1[C@H:33]([CH3:34])[N:32]([C:31]([N:6]([CH3:5])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:35])[C:1]1=[O:2])=[O:28])([CH3:25])([CH3:24])[CH3:23]

Participants

8

Reactant 4

HCID 6371PhosgeneHCID 8471Triethylamine3×HCID 5069406Tert-butyl 2-(methylamino)acetateHCID 13155285tert-Butyl ((2S,3S)-2-methyl-4-oxoazetidin-3-yl)carbamate

Product 1

HCID 131714548(3S-trans)-N-[[3-[[t-Butoxycarbonyl]amino]-4-methyl-2-oxo-1-azetidinyl]carbonyl]-N-methylglycine, t-butyl ester

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A solution of phosgene in toluene (1.35 ml of a 20% solution, 2.698 mmol) was cooled to -25° C. under an argon atmosphere. A solution of N-methylglycine, t-butyl ester (218 mg, 1.498 mmol) and triethylamine (251 μl, 1.798 mmol) in dichloromethane (2 ml) was added dropwise over 5 minutes. The reaction was stirred for 1 hour at -25° C. (after 15 minutes an additional 0.2 ml of dichloromethane was added to facilitate stirring). The volatiles were removed starting at -25° C. and slowly by warming to room temperature. The residue was dissolved in methylene chloride (5 ml), cooled to 0° C. and treated with (3S-trans)-3-[[t-butoxycarbonyl]amino]-4-methyl-2-azetidinone (300 mg, 1.498 mmol; pre-dried over P2O5 at 25° C. under high vacuum), 4-dimethylaminiopyridine (18 mg, 0.149 mmol), and triethylamine (251 μl, 1.798 mmol). The resulting mixture was warmed to room temperature, stirred for 36 hours, treated with additional triethylamine (502 μl), and refluxed for 5 hours. The reaction was cooled, diluted with ethyl acetate, washed with pH 4.5 KH2PO4, and with brine, and then dried over sodium sulfate. Filtration and concentration in vacuo produced 525 mg of an oil which was chromatographed on 21 g of silica gel (230-400 mesh). Elution with 40% ethyl acetate-hexane gave 356 mg of the title compound as a white solid.

Workup

  1. additionwas added
  2. customThe volatiles were removed
  3. customstarting at -25° C.
  4. dissolutionThe residue was dissolved in methylene chloride (5 ml)
  5. temperaturecooled to 0° C.
  6. temperatureThe resulting mixture was warmed to room temperature
  7. stirringstirred for 36 hours
  8. temperaturerefluxed for 5 hours
  9. temperatureThe reaction was cooled
  10. washwashed with pH 4.5 KH2PO4
  11. dry with materialwith brine, and then dried over sodium sulfate
  12. filtrationFiltration and concentration in vacuo

Sources & evidence

ORD record
ord-25da6eb50cac4975a77a2a733776fabe
Source dataset
uspto-grants-1986_03
Patent number
US04576749

Reaction notes

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