Methanol → 8-(1,1-Dimethylethyl) 2-methyl 3-hydroxy-8-azabicyclo[3.2.1]oct-2-ene-2,8-dicarboxylate

HRID 1895038Notes

Reaction equation

HRID 1895038 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[O:16])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O:20]C)[O:18][CH3:19].[H-].[Na+].CO>C1CCCCC1.O>[CH3:19][O:18][C:17]([C:12]1[CH:13]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([CH2:10][C:11]=1[OH:16])[CH2:15][CH2:14]2)=[O:20]

Participants

7

Reactant 4

HCID 887MethanolHCID 12021Dimethyl CarbonateHCID 24758Sodium hydrideHCID 2794767tert-Butyl 3-oxo-8-azabicyclo(3.2.1)octane-8-carboxylate

Product 1

HCID 580172918-(1,1-Dimethylethyl) 2-methyl 3-hydroxy-8-azabicyclo[3.2.1]oct-2-ene-2,8-dicarboxylateYield 87.7%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8078CyclohexaneSolvent

Procedure

3-Oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester from Step 1 (14.1 g, 62 mmol) was dissolved in cyclohexane (550 mL), to which was added dimethyl carbonate (12.4 g, 137 mmol), followed by sodium hydride (5.0 g, 125 mmol) and methanol (0.2 mL). The reaction mixture was stirred at reflux for 15 hours, then cooled to room temperature, and water (25 mL) was added. The reaction mixture was concentrated under reduced pressure to a volume of 50 mL, which was then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate/hexane) to provide 3-hydroxy-8-azabicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester as a light yellow oil (15.4 g, 87% yield).

Workup

  1. temperatureat reflux for 15 hours
  2. concentrationThe reaction mixture was concentrated under reduced pressure to a volume of 50 mL, which
  3. customwas then partitioned between ethyl acetate and saturated aqueous ammonium chloride
  4. washThe combined organic extracts were washed with water and brine
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by flash chromatography (silica gel, ethyl acetate/hexane)

Sources & evidence

ORD record
ord-8da08354afe5415294aa82fe1434d9d8
Source dataset
uspto-grants-2013_08
Patent number
US08513425B2

Reaction notes

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