2,2,2-Trifluoroethanol → Bicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 2-[[(1,1-dimethylethoxy)carbonyl]amino]-4-oxo-, 2,6-bis(1,1-dimethylethyl) ester, (1S,2S,5R,6R)-

HRID 2242298Notes

Reaction equation

HRID 2242298 reaction equation
CC([O-])(C)C.[K+].[Br-].[C:8]([O:12][C:13](=[O:20])[CH2:14][S+]1CCCC1)([CH3:11])([CH3:10])[CH3:9].C(O)C(F)(F)F.[C:27]([O:31][C:32]([NH:34][C@:35]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH:39]=[CH:38][C:37](=[O:40])[CH2:36]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(#N)C.CC(OC)(C)C>[C:44]([O:43][C:41]([C@:35]1([NH:34][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:36][C:37](=[O:40])[C@@H:38]2[C@H:39]1[C@H:14]2[C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:20])=[O:42])([CH3:47])([CH3:46])[CH3:45]

Participants

7

Reactant 4

HCID 64092,2,2-Trifluoroethanol2×HCID 23665647Potassium tert-butoxideHCID 597129231,1-Dimethylethyl (1S)-1-[[(1,1-dimethylethoxy)carbonyl]amino]-4-oxo-2-cyclopentene-1-carboxylateHCID 85844044Thiophenium, 1-[2-(1,1-dimethylethoxy)-2-oxoethyl]tetrahydro-, bromide (1:1)

Product 1

HCID 59712878Bicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 2-[[(1,1-dimethylethoxy)carbonyl]amino]-4-oxo-, 2,6-bis(1,1-dimethylethyl) ester, (1S,2S,5R,6R)-

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolvent2×HCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
4 °C

Procedure

Add KOtBu (42 mL, 42 mmol, 1 M solution in THF, 2.5 equiv) to a 0° C. solution of 1-(2-tert-butoxy-2-oxoethyl)tetrahydrothiophenium bromide (11.9 g, 42 mmol, 2.5 equiv., Preparation 48) in acetonitrile (30 mL) under N2 over 10 minutes keeping the temperature below 5° C. Stir the milky solution cold for 1.5 hours. Add trifluoroethanol (6.9 g, 69 mmol, 4.1 equiv) dropwise. Add a solution of (1S)-1-(tert-butoxycarbonylamino)-1-(tert-butoxycarbonyl)-cyclopent-4-en-3-one (5 g, 16.8 mmol, Preparation 47) and trifluoroethanol (13.3 g, 132 mmol, 7.9 equiv) in acetonitrile (20 mL), over 5 minutes, maintaining the temperature at 3-5° C. Stir the solution for 4.5 hours at 0-5° C. Add MTBE (155 mL) and 120 (80 mL) to the cold reaction mixture. Separate the layers and wash the organic layer with H2O (50 mL), then 20% brine (50 mL). Concentrate the organic layer via atmospheric pressure distillation to approximately 30 mL. Add heptane (100 mL) and concentrate the solution. Add additional heptane as needed until the vapor temperature of the distillate reaches 93° C. Add THF (65 mL) to yield a solution of the title compound.

Workup

  1. customthe temperature below 5° C
  2. waitover 5 minutes
  3. stirringStir the solution for 4.5 hours at 0-5° C
  4. customSeparate the layers
  5. washwash the organic layer with H2O (50 mL)
  6. concentrationConcentrate the organic layer
  7. distillationvia atmospheric pressure distillation to approximately 30 mL
  8. concentrationAdd heptane (100 mL) and concentrate the solution
  9. additionAdd additional heptane
  10. customas needed until the vapor temperature of the distillate reaches 93° C

Sources & evidence

ORD record
ord-b36dcfa7c1a94613813337c7766905e0
Source dataset
uspto-grants-2010_03
Patent number
US07671082B2

Reaction notes

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