Acetic Acid → Di-tert-butyl (1S,2R,5R,6R)-2-(tert-butoxycarbonylamino)-3-methylene-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate

HRID 469920Notes

Reaction equation

HRID 469920 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:14](=[CH:15]N(C)C)[C:13](=[O:19])[C@@H:12]2[C@H:10]1[C@H:11]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)C.OP(O)(O)=O>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:14](=[CH2:15])[C:13](=[O:19])[C@@H:12]2[C@H:10]1[C@H:11]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 1004Phosphoric AcidHCID 8471TriethylamineHCID 21225700DiisobutylaluminumhydrideHCID 86665754Di-tert-butyl (1S,2R,5R,6R)-2-(tert-butoxycarbonylamino)-3-(dimethylaminomethylene)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate

Product 1

HCID 67643282Di-tert-butyl (1S,2R,5R,6R)-2-(tert-butoxycarbonylamino)-3-methylene-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylateYield 99.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-47 °C

Procedure

To a solution of di-tert-butyl (1S,2R,5R,6R)-2-(tert-butoxycarbonylamino)-3-(dimethylaminomethylene)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (620.4 g, 1.33 mol) in dry tetrahydrofuran (12 L), triethylamine (277.3 ml, 1.99 mol) is added at room temperature under nitrogen. The mixture is cooled to −47° C. and diisobutylaluminum hydride (1M in hexane, 2.06 L, 2.06 mol) is added dropwise over 2 hours. The resulting mixture is stirred at −47° C. After 1 hour 15 minutes, acetic acid (118 ml, 2.06 mol) is dropwise added at −47° C., warmed to room temperature, and then stirred overnight. Add 20% H3PO4 in water until pH=2. Separate the organic phase and extract the aqueous phase with ethyl acetate (2×1.7 L). The combined organic phases are washed successively with 10% aqueous HCl (1.5 L), water (1.5 L), and brine (1.5 L), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a solid. The resulting solid is triturated with water (3.2 L), collected by filtration, and then dried to yield the title compound (558.2 g, yield 99%). HPLC-MS: 97.4%.

Workup

  1. temperaturewarmed to room temperature
  2. stirringstirred overnight
  3. customSeparate the organic phase
  4. extractionextract the aqueous phase with ethyl acetate (2×1.7 L)
  5. washThe combined organic phases are washed successively with 10% aqueous HCl (1.5 L), water (1.5 L), and brine (1.5 L)
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto yield a solid
  10. customThe resulting solid is triturated with water (3.2 L)
  11. filtrationcollected by filtration
  12. customdried

Sources & evidence

ORD record
ord-7cbc89a3653f42a286c8143087509262
Source dataset
uspto-grants-2014_01
Patent number
US08629169B2

Reaction notes

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