Diisopropylethylamine → p-nitrobenzyl (1R,5S,6S)-2-[1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)piperidin-4-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate

HRID 891481Notes

Reaction equation

HRID 891481 reaction equation
C([S:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)[CH2:7][CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:42]2[C@H:43]([CH3:66])[C@H:44]3[C@@H:61]([C@H:62]([OH:64])[CH3:63])[C:60](=[O:65])[N:45]3[C:46]=2[C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[CH2:19]([O:18][C:16]([C:14]1[N:15]=[C:11]([N:8]2[CH2:7][CH2:6][CH:5]([S:4][C:42]3[C@H:43]([CH3:66])[C@@H:44]4[C@@H:61]([C@H:62]([OH:64])[CH3:63])[C:60](=[O:65])[N:45]4[C:46]=3[C:47]([O:49][CH2:50][C:51]3[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=3)=[O:48])[CH2:10][CH2:9]2)[S:12][CH:13]=1)=[O:17])[CH3:20]

Participants

9

Reactant 5

HCID 81531DiisopropylethylamineHCID 165591Hydrazine, acetate (1:1)HCID 516892Sodium BicarbonateHCID 222429214-Acetylthio-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)piperidineHCID 131720384p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate

Product 1

HCID 131725298p-nitrobenzyl (1R,5S,6S)-2-[1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)piperidin-4-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylateYield 38%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 4-acetylthio-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)piperidine (400 mg, 1.27 mmol) (obtained as described in Reference Example 13) in dimethylformamide (12 ml) was added hydrazine acetate (152 mg, 1.65 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 2.5 hours. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (755 mg, 1.27 mmol) in acetonitrile (21 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (1.11 ml, 6.37 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane: ethyl acetate (1:2) and ethyl acetate as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)piperidin-4-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate as a pale yellow solid (296 mg, yield 38%).

Workup

  1. customthe completion of the reaction
  2. stirringThe mixture was stirred overnight
  3. additionwere added to the reaction mixture
  4. stirringThe resulting mixture was shaken in a separatory funnel
  5. customthe ethyl acetate layer was separated
  6. washwashed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution
  7. dry with materialdried over anhydrous magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified by chromatography on a silica gel column

Sources & evidence

ORD record
ord-fce6a9b102c9454285fba13fc67f41e3
Source dataset
uspto-grants-2006_02
Patent number
US07001897B2

Reaction notes

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