Sodium Hydroxide → (1r,5s)-6,6-Dimethyl-3-oxabicyclo[3.1.0]hexan-2-one

HRID 2078488Notes

Reaction equation

HRID 2078488 reaction equation
C(OC[CH:6]1[CH:8]([C:9]([O:11][CH2:12]C)=[O:10])[C:7]1([CH3:15])[CH3:14])(=O)C.CC[C@@H]1N2C(N(C3C=CC(F)=CC=3)C(=O)[C@H]2CC2C3C(NC1=2)=CC=CC=3)=O.[OH-].[Na+].OCC1C(C(O)=O)C1(C)C.CC1(C)C2C1COC2=O.OC[C@H]1[C@H](C(O)=O)C1(C)C>C1(C)C=CC=CC=1.O>[CH3:15][C:7]1([CH3:14])[C@H:8]2[C@@H:6]1[CH2:12][O:11][C:9]2=[O:10]

Participants

9

Reactant 6

HCID 14798Sodium HydroxideHCID 11535853Ethyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate2×HCID 117151993-Hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acidHCID 118153586,6-Dimethyl-3-oxabicyclo[3.1.0]hexan-2-oneHCID 24978618trans-BodyHCID 67120920(1S,3S)-3-(Hydroxymethyl)-2,2-dimethylcyclopropane-1-carboxylic acid

Product 1

HCID 11094620(1r,5s)-6,6-Dimethyl-3-oxabicyclo[3.1.0]hexan-2-one

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent2×

Conditions

Temperature
50 °C

Procedure

To 13.5 kg of a solution containing 8.53 kg of ethyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate obtained in Production Example (39.8 mol, cis body/trans body ratio was 83.4/16.6, (1R)-cis body had an optical purity of 93.4% ee), 9.1 kg of water was added and the temperature thereof was raised up to 50° C., then, 24.2 kg of a 28% sodium hydroxide aqueous solution was dropped over a period of 4 hours, and the mixture was thermally kept at the same temperature for 2 hours. It was confirmed that ethyl 3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate disappeared and was converted into 3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid, then, to this solution was added 25.6 kg of toluene and the solution was mixed and separated, and the organic layer was removed. Further, to the aqueous layer was added 17.1 kg of toluene and the solution was mixed and separated, and the organic layer was removed likewise. To the resultant aqueous layer was added 21.8 kg of 35% hydrochloric acid at 20° C. and the mixture was thermally kept for 3 hours. It was confirmed that cis-3-hydroxymethyl-2,2-dimethyl-cyclopropanecarboxylic acid was converted into 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one, then, a 28% sodium hydroxide aqueous solution was dropped to adjust pH of the solution to 7. An extraction operation was repeated three times from this solution with 17.1 kg of toluene, and the resultant three toluene solutions were combined, to obtain 55.7 kg of a toluene solution containing 4.05 kg of 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one (32.1 mol, yield based on ethyl cis-3-acetoxymethyl-2,2-dimethylcyclopropanecarboxylate: 96.7%). In this toluene solution, trans-3-hydroxymethyl-2,2-dimethylcyclopropanecarboxylic acid was not detected.

Workup

  1. additionwas added
  2. additionthe solution was mixed
  3. customseparated
  4. customthe organic layer was removed
  5. additionFurther, to the aqueous layer was added 17.1 kg of toluene
  6. additionthe solution was mixed
  7. customseparated
  8. customthe organic layer was removed likewise
  9. additionTo the resultant aqueous layer was added 21.8 kg of 35% hydrochloric acid at 20° C.
  10. waitthe mixture was thermally kept for 3 hours
  11. additiona 28% sodium hydroxide aqueous solution was dropped
  12. customto obtain 55.7 kg of a toluene solution

Sources & evidence

ORD record
ord-81f1294f187947f8a0e784b1e6a77055
Source dataset
uspto-grants-2011_04
Patent number
US07928253B2

Reaction notes

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