Water → 3-[(E)-1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid triethylammonium salt

HRID 581229Notes

Reaction equation

HRID 581229 reaction equation
N[C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6](/[CH:14]=[C:15]1/[C:16](=[O:24])[N:17]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH2:18][CH2:19]/1)=[C:7]2[C:11]([OH:13])=[O:12].CC(O)C.O.C(N(CC)CC)C>CN(C)C=O>[CH2:16]([NH+:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH3:15].[CH:21]1([CH2:20][N:17]2[CH2:18][CH2:19]/[C:15](=[CH:14]\[C:6]3[CH2:5][S:4][CH:3]4[N:8]([C:9](=[O:10])[CH2:2]4)[C:7]=3[C:11]([O-:13])=[O:12])/[C:16]2=[O:24])[CH2:23][CH2:22]1

Participants

6

Reactant 4

HCID 962WaterHCID 3776IsopropanolHCID 8471TriethylamineHCID 10689147(E)-(6R,7R)-7-Amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Product 1

HCID 1317211873-[(E)-1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid triethylammonium saltYield 77%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
2 °C

Procedure

To a stirred suspension of 22.78 g (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (65.2 mmol) in 160 ml dimethylformamide was added under argon 9.1 ml triethylamine (65.2 mmol) at 10° C. After 30 min, to the solution was added 48 ml 2-propanol and 3.9 ml water causing the starting material to precipitate partially. The suspension was cooled to 2° C. and over 5 min was added in portions 36.68 g activated ester (Z)-(2-Aminothiazol-4-yl)-trityloxyiminoacetic acid diethoxythiophosphoryl ester (66.5 mmol). Stirring was continued at room temperature with exclusion of light for 17 h. The reaction was followed by HPLC. To the slightly turbid reaction mixture was added over 2 min 9.2 ml triethylamine (65.2 mmol, 1.0 eq) resulting in a clear, yellow solution. Reference material was added and after ca. 15 min, the reaction mixture became turbid, indicating the onset of crystallization. Stirring at room temperature was continued for 60 min and then 330 ml ethylacetate was added dropwise over 90 min. To drive crystallization to completion the suspension was cooled to 2° C. and stirred for 3 h at this temperature. The suspension was filtered. The crystalline product was washed with 3×100 ml ice-cold ethylacetate and dried to constant weight. The cephalosporin (6R, 7R)-7-[(Z)-2-(2-Aminothiazol-4-yl)-2-trityloxyimino-acetylamino)]-3-[(E)-1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid triethylammonium salt was obtained as an off-white solid (51.56 g, yield=77%, HPLC=100 area %) and was stored under Ar at 4° C. No further purification was necessary and the product was used as isolated for the next step.

Workup

  1. additionwas added under argon 9.1 ml triethylamine (65.2 mmol) at 10° C
  2. customto precipitate partially
  3. waitwas continued at room temperature with exclusion of light for 17 h
  4. customTo the slightly turbid reaction mixture
  5. customresulting in a clear, yellow solution
  6. additionReference material was added and after ca. 15 min
  7. customthe onset of crystallization
  8. stirringStirring at room temperature
  9. waitwas continued for 60 min
  10. addition330 ml ethylacetate was added dropwise over 90 min
  11. customcrystallization to completion the suspension
  12. temperaturewas cooled to 2° C.
  13. stirringstirred for 3 h at this temperature
  14. filtrationThe suspension was filtered
  15. washThe crystalline product was washed with 3×100 ml ice-cold ethylacetate
  16. customdried to constant weight

Sources & evidence

ORD record
ord-a0946d96977b4eefad64030f9f45a0a9
Source dataset
uspto-grants-1999_07
Patent number
US05919939

Reaction notes

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