Ethanol → Ethyl-6-chloro-7-hydroxy-3,4-dihydro-2H-chromene-4-carboxylate

HRID 1021336Notes

Reaction equation

HRID 1021336 reaction equation
[CH2:1](O)[CH3:2].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[OH:15])[O:11][CH2:10][CH2:9][CH:8]2[C:16]([OH:18])=[O:17].S(=O)(=O)(O)O>C(OCC)(=O)C>[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[OH:15])[O:11][CH2:10][CH2:9][CH:8]2[C:16]([O:18][CH2:1][CH3:2])=[O:17]

Participants

5

Reactant 3

HCID 702EthanolHCID 1118Sulfuric AcidHCID 670804281202889-63-1

Product 1

HCID 53393319Ethyl-6-chloro-7-hydroxy-3,4-dihydro-2H-chromene-4-carboxylateYield 43%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Procedure

A 20-liter 4-neck round-bottom flask was charged with ethanol (8.6 L) and crude 6-chloro-7-hydroxychroman-4-carboxylic acid (1.70 kg, 7.44 mol) and the resulting mixture was stirred at ambient temperature. Concentrated sulfuric acid (397 mL) was added over 10 minutes. The resulting mixture was stirred and heated to reflux for 16 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (9.0 mL). The resulting mixture was washed with brine (2×12 L). The brine washes were combined and extracted with ethyl acetate (4 L). The ethyl acetate layer was washed with brine (2 L). The organic layers were combined and dried over sodium sulfate, then concentrated under reduced pressure at a temperature below 50° C. The residue was purified by chromatography on silica gel (18 kg), eluting with 85:15 hexanes:ethyl acetate (235 L), to afford ethyl 6-chloro-7-hydroxychroman-4-carboxylate as a white powder (822 g, 43% yield). MS (apci) m/z=255.1 (M−H).

Workup

  1. stirringThe resulting mixture was stirred
  2. temperatureheated
  3. temperatureto reflux for 16 hours
  4. temperatureThe reaction mixture was cooled to ambient temperature
  5. washThe resulting mixture was washed with brine (2×12 L)
  6. extractionextracted with ethyl acetate (4 L)
  7. washThe ethyl acetate layer was washed with brine (2 L)
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated under reduced pressure at a temperature below 50° C
  10. customThe residue was purified by chromatography on silica gel (18 kg)
  11. washeluting with 85:15 hexanes

Sources & evidence

ORD record
ord-39daaffc3adf4f9dafb605dd44b4c7b4
Source dataset
uspto-grants-2014_05
Patent number
US08716498B2

Reaction notes

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