Diphenyl chlorophosphate → 4-Nitrobenzyl (1R,5S,6S)-2-{(2S,4S)-2-[4-(2-carbamoyloxyethyl)-1-piperazinylcarbonyl]-1-(4-nitro-benzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate

HRID 1033676Notes

Reaction equation

HRID 1033676 reaction equation
P(Cl)(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(N(C(C)C)CC)(C)C.[OH:27][C@@H:28]([C@H:30]1[C:51](=[O:52])[N:32]2[CH:33]([C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)=[O:39])[C:34](=O)[C@H:35]([CH3:36])[C@H:31]12)[CH3:29].FC(F)(F)S(O)(=O)=O.[C:61]([O:64][CH2:65][CH2:66][N:67]1[CH2:72][CH2:71][N:70]([C:73]([C@@H:75]2[CH2:79][C@H:78]([SH:80])[CH2:77][N:76]2[C:81]([O:83][CH2:84][C:85]2[CH:90]=[CH:89][C:88]([N+:91]([O-:93])=[O:92])=[CH:87][CH:86]=2)=[O:82])=[O:74])[CH2:69][CH2:68]1)(=[O:63])[NH2:62]>C(#N)C>[C:61]([O:64][CH2:65][CH2:66][N:67]1[CH2:68][CH2:69][N:70]([C:73]([C@@H:75]2[CH2:79][C@H:78]([S:80][C:34]3[C@H:35]([CH3:36])[C@@H:31]4[C@@H:30]([C@H:28]([OH:27])[CH3:29])[C:51](=[O:52])[N:32]4[C:33]=3[C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)=[O:39])[CH2:77][N:76]2[C:81]([O:83][CH2:84][C:85]2[CH:86]=[CH:87][C:88]([N+:91]([O-:93])=[O:92])=[CH:89][CH:90]=2)=[O:82])=[O:74])[CH2:71][CH2:72]1)(=[O:63])[NH2:62]

Participants

6

Reactant 4

HCID 75654Diphenyl chlorophosphateHCID 81531Diisopropylethylamine2×HCID 98853021-Azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-, (4-nitrophenyl)methyl ester, (4R,5R,6S)-HCID 86747840(2S,4S)-2-[4-(2-Carbamoyloxyethyl)-1-piperazinylcarbonyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethanesulfonate

Product 1

HCID 570435664-Nitrobenzyl (1R,5S,6S)-2-{(2S,4S)-2-[4-(2-carbamoyloxyethyl)-1-piperazinylcarbonyl]-1-(4-nitro-benzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylateYield 28.6%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

91 μl of diphenyl phosphorochloridate and 77 μl of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 152 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 2.0 ml of anhydrous acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. At the end of this time, 176 μl of diisopropylethylamine and a solution of 318 mg of (2S,4S)-2-[4-(2-carbamoyloxyethyl)-1-piperazinylcarbonyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethanesulfonate [prepared as described in step (1) above] in 2.0 ml of anhydrous acetonitrile were then added dropwise to the mixture, whilst ice-cooling, and the mixture was stirred at the same temperature for 2 hours. At the end of this time, the reaction mixture was allowed to stand overnight in a refrigerator, after which it was freed from the solvent by distillation under reduced pressure. The resulting residue was mixed with an aqueous solution of sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by chromatography through a Lobar column (a product of Merk & Co., Inc., LiChroprep Si60, size B). Those fractions eluted with a 5:1 by volume mixture of ethyl acetate and methanol were collected and concentrated by evaporation under reduced pressure, to give 99 mg of the title compound as a powder.

Workup

  1. temperaturecooling
  2. stirringthe mixture was stirred at the same temperature for 2 hours
  3. waitto stand overnight in a refrigerator
  4. distillationafter which it was freed from the solvent by distillation under reduced pressure
  5. additionThe resulting residue was mixed with an aqueous solution of sodium hydrogencarbonate
  6. extractionextracted with ethyl acetate
  7. dry with materialThe extract was dried over anhydrous magnesium sulfate
  8. customthe solvent was removed by distillation under reduced pressure
  9. customThe resulting residue was purified by chromatography through a Lobar column (a product of Merk & Co
  10. washThose fractions eluted with a 5:1 by volume mixture of ethyl acetate and methanol
  11. customwere collected
  12. concentrationconcentrated by evaporation under reduced pressure

Sources & evidence

ORD record
ord-732ef6fdedda42d3bff9a1c20b964560
Source dataset
uspto-grants-1994_05
Patent number
US05310735

Reaction notes

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