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Potassium tert-butoxide → Diethyl (1S,2S,5R,6S)-2-benzyloxycarbonylamino-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate

HRID 2037297
Notes
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Reaction equation

HRID 2037297 reaction equation
[CH3:1]C(C)([O-])C.[K+].[CH2:7]([O:14][C:15]([NH:17][C@@:18]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:23][C:22](=O)[C@@H:21]2[C@H:19]1[C@H:20]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH2:7]([O:14][C:15]([NH:17][C@@:18]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:23][C:22](=[CH2:1])[C@@H:21]2[C@H:19]1[C@H:20]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 2

HCID 23665647Potassium tert-butoxideHCID 86691270HCID 86691270, compound

Product 1

HCID 86691272Diethyl (1S,2S,5R,6S)-2-benzyloxycarbonylamino-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate

Reagents, catalysts & solvents 3

HCID 74505Methyltriphenyliphosphonium bromideCatalystHCID 8028Tetrahydrofuran
Solvent
3×
HCID 8857Ethyl AcetateSolvent

Procedure

Under a nitrogen atmosphere, combine methyl-triphenylphosphonium bromide (67.4 g, 184.9 mmol) and tetrahydrofuran (300 mL) with agitation. Add a solution of potassium tert-butoxide (1M) in tetrahydrofuran, 184.9 mL, 184.9 mmol) to the reaction mixture over 15 minutes and stir the resulting slurry at ambient temperature for 3 hours. Dissolve diethyl (1S,2S,5R,6R)-2-benzyloxycarbonylamino-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (12.3 kg, 31.6 mol) in tetrahydrofuran (120 mL) and add to the reaction mixture over 1 hour, maintaining the reaction temperature below 30° C. Stir the resulting slurry overnight at ambient temperature, then dilute with ethyl acetate (600 mL) and quench with water (300 mL). After stirring the biphasic mixture for 30 minutes, separate the layers and wash the organics with water (300 mL) followed by 0.25M HCl (300 mL). Dry the organics over Na2SO4, filter, and concentrate in vacuo (45° C.) to afford the crude product as a dark oil (111.0 g). Purify the material by silica gel plug chromatography (1 Kg Kieselgel-60, 4 L 15% EtOAc in heptanes, then 10 L 30% EtOAc in heptanes) to afford the title compound as a clear oil (37.3 g, 87.9% potency, 54.9%). MS (m/z): 388 (M+1).

Workup

  1. temperaturemaintaining the reaction temperature below 30° C
  2. stirringStir the resulting slurry overnight at ambient temperature
  3. customquench with water (300 mL)
  4. stirringAfter stirring the biphasic mixture for 30 minutes
  5. customseparate the layers
  6. washwash the organics with water (300 mL)
  7. dry with materialDry the organics over Na2SO4
  8. filtrationfilter
  9. concentrationconcentrate in vacuo (45° C.)
  10. customto afford the crude product as a dark oil (111.0 g)
  11. customPurify the material by silica gel plug chromatography (1 Kg Kieselgel-60, 4 L 15% EtOAc in heptanes

Sources & evidence

ORD record
ord-d12d00ab1bab438983860e934fc49770
Source dataset
uspto-grants-2013_11
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08575214B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes