Hydrochloric Acid → (1R,2R)-ethyl 1,2-bis(hydroxymethyl)cyclopropanecarboxylate

HRID 578744Notes

Reaction equation

HRID 578744 reaction equation
C(O)C.[O:4]=[C:5]1[O:10][CH2:9][C@H:8]2[C@:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7]2.[BH4-].[Na+].Cl>C(OCC)(=O)C>[OH:4][CH2:5][C@@:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][C@H:8]1[CH2:9][OH:10]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 702EthanolHCID 4311764Sodium borohydrideHCID 10654701ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate

Product 1

HCID 10725903(1R,2R)-ethyl 1,2-bis(hydroxymethyl)cyclopropanecarboxylateYield 47.4%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
10 °C

Procedure

In a reactor, ethanol (82.4 L) followed by ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate (10.3 kg, 64.6 mol) were added and cooled to 10° C. Sodium borohydride (1.85 kg, 51.7 mol) was added in lots over a period of 1 hour by maintaining the reaction temperature between 10-15° C. The reaction temperature was raised to 20-25° C. and maintained for 1 hour. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 0-5° C. The pH of the reaction mass was adjusted to 7.0 using 1.5 N aqueous HCl at 0-5° C. during 1 hour. Ethyl acetate (34.0 L) was added to the reaction mass and the solid was filtered. The clear filtrate was distilled under reduced pressure at 40-45° C. to remove most of the solvent and the concentrate was dissolved in dichloromethane (103.0 L). The dichloromethane layer was washed with water (2×10.5 L). The aqueous layer was re-extracted with dichloromethane (3×10.5 L). The dichloromethane layers were combined and washed with brine (1×15.0 L). The organic layer was collected and distilled to remove most of the solvent at 40-45° C. under reduced pressure. The concentrate was passed over silica gel 60-120 mesh plug column using petroleum ether followed by 100% ethyl acetate as eluent to afford 5.0 kg (47.4%) of the title compound (2c).

Workup

  1. additionwere added
  2. temperatureby maintaining the reaction temperature between 10-15° C
  3. temperatureThe reaction temperature was raised to 20-25° C.
  4. temperaturemaintained for 1 hour
  5. customAfter completion of the reaction
  6. temperaturethe reaction mass was cooled to 0-5° C
  7. filtrationthe solid was filtered
  8. distillationThe clear filtrate was distilled under reduced pressure at 40-45° C.
  9. customto remove most of the solvent
  10. dissolutionthe concentrate was dissolved in dichloromethane (103.0 L)
  11. washThe dichloromethane layer was washed with water (2×10.5 L)
  12. extractionThe aqueous layer was re-extracted with dichloromethane (3×10.5 L)
  13. washwashed with brine (1×15.0 L)
  14. customThe organic layer was collected
  15. distillationdistilled
  16. customto remove most of the solvent at 40-45° C. under reduced pressure

Sources & evidence

ORD record
ord-feab27af6a0d4251a7ba9b92e1f1edc5
Source dataset
uspto-grants-2015_05
Patent number
US09040699B2

Reaction notes

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