Phosgene → (S)-N-[[3-[[(Phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]N-methyl-DL-alanine, phenylmethyl ester

HRID 482925Notes

Reaction equation

HRID 482925 reaction equation
[C:1](Cl)(Cl)=[O:2].[CH3:5][NH:6][CH:7]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH3:8].C(N(CC)CC)C.[C:26]1([CH2:32][O:33][C:34]([NH:36][C@H:37]2[CH2:40][NH:39][C:38]2=[O:41])=[O:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C1C=CC=CN=1)C>C1(C)C=CC=CC=1.ClCCl>[C:26]1([CH2:32][O:33][C:34]([NH:36][CH:37]2[CH2:40][N:39]([C:38]([N:6]([CH3:5])[C@H:7]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH3:8])=[O:41])[C:1]2=[O:2])=[O:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1

Participants

8

Reactant 5

HCID 6371PhosgeneHCID 8471Triethylamine2×HCID 218852-DimethylaminopyridineHCID 12834624benzyl N-[(3S)-2-oxoazetidin-3-yl]carbamateHCID 15640239N-methyl-DL-alanine, benzyl ester

Product 1

HCID 131714547(S)-N-[[3-[[(Phenylmethoxy)carbonyl]amino]-2-oxo-1-azetidinyl]carbonyl]N-methyl-DL-alanine, phenylmethyl ester

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A solution of phosgene in toluene (4.7 ml of a 20% solution, 9.36 mmol) was cooled to -25° C. under argon. While stirring, a solution (pre-cooled to 0° C.) of N-methyl-DL-alanine, benzyl ester (1.0 g, 5.2 mmol) and triethylamine (870 μl, 6.25 mmol) in dichloromethane (5 ml) was added over 5 minutes maintaining the temperature at -20° to -25° C. After stirring at -25° C. for 1 hour, solvent and excess phosgene were removed in vacuo. The residue was dissolved in dichloromethane (12 ml), cooled to 0° C. and then (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (1.15 g, 5.2 mmol), dimethylaminopyridine (63 mg, 0.52 mmol), and triethylamine (870 μl, 6.2 mmol) were added sequentially. Stirring was continued for 10 minutes at 0° C. and then overnight at room temperature. After refluxing for an additional 7 hours, the mixture was again stirred overnight at room temperature. The mixture was washed with water, dried (Na2SO4) and solvent was removed in vacuo. The resulting oil was chromatographed on silica gel eluting with a 4:6 ethyl acetate:hexane mixture. The desired product was obtained as an oil (580 mg).

Workup

  1. temperaturemaintaining the temperature at -20° to -25° C
  2. stirringAfter stirring at -25° C. for 1 hour
  3. customsolvent and excess phosgene were removed in vacuo
  4. dissolutionThe residue was dissolved in dichloromethane (12 ml)
  5. stirringStirring
  6. customovernight
  7. customat room temperature
  8. temperatureAfter refluxing for an additional 7 hours
  9. waitthe mixture was again stirred overnight at room temperature
  10. washThe mixture was washed with water
  11. dry with materialdried (Na2SO4) and solvent
  12. customwas removed in vacuo
  13. customThe resulting oil was chromatographed on silica gel eluting with a 4:6 ethyl acetate

Sources & evidence

ORD record
ord-cba0cb31a43d4dd6a17e49c9769038e5
Source dataset
uspto-grants-1986_03
Patent number
US04576749

Reaction notes

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