Water → (R)-4,4,4-trifluoro-2-methyl-N-[(S)-1-phenylethyl]butyramide

HRID 327813Notes

Reaction equation

HRID 327813 reaction equation
[F:1][C:2]([F:18])([F:17])[CH2:3][CH:4]([CH3:16])[C:5]([NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CC(C)([O-])C.[K+].O.C1(C)C=CC=CC=1>O1CCCC1>[F:1][C:2]([F:17])([F:18])[CH2:3][C@@H:4]([CH3:16])[C:5]([NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6]

Participants

6

Reactant 4

HCID 962WaterHCID 1140TolueneHCID 23665647Potassium tert-butoxideHCID 54100298HCID 54100298, compound

Product 1

HCID 10967206(R)-4,4,4-trifluoro-2-methyl-N-[(S)-1-phenylethyl]butyramideYield 32%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
40 °C

Procedure

10 g of 4,4,4-trifluoro-2-methyl-N-[(S)-1-phenylethyl]butyramide (diastereomer ratio 2(S):1(R), prepared by a method similar to that described in step c)above) was dissolved in tetrahydrofuran (25 ml) with stirring. Potassium t-butoxide (2.02 g) was then added, together with tetrahydrofuran (5 ml). The resultant solution was then stirred for one hour, by which time complete equilibration of the diastereomers had occured, as monitored by HPLC analysis. Water was then added with cooling to maintain the temperature at 20°-25° C. The solution was then stirred for 10 minutes, and then toluene (25 ml) was added, and the stirring was continued for a further 15 minutes. The organic layer was then separated, washed with water (12.5 ml) and concentrated by distillation at atmospheric pressure to a temperature of 110° C. The volume was adjusted to 80 ml by adding toluene, and the mixture heated under reflux. Petroleum ether (b.p. 100°-120° C.) (80 ml) was then added. The solution was then allowed to cool to 40° C., seeded with (R)-4,4,4-trifluoro-2-methyl-N-[(S)-1-phenylethyl]butyramide and held at 40° C. for 2 hours. The mixture was then allowed to cool to 30° C., and was stirred overnight. The crystalline product was then filtered off, washed with petroleum ether (b.p. 100°-120° C.) and dried at 65° C. to afford 3.20 g (32%) of (R)-4,4,4-trifluoro-2-methyl-N-[(S)-1-phenylethyl]butyramide contaminated with about 6% of the undesired (S) diastereomer. ##STR2##

Workup

  1. temperaturewith cooling
  2. temperatureto maintain the temperature at 20°-25° C
  3. stirringThe solution was then stirred for 10 minutes
  4. customThe organic layer was then separated
  5. washwashed with water (12.5 ml)
  6. concentrationconcentrated by distillation at atmospheric pressure to a temperature of 110° C
  7. additionby adding toluene
  8. temperaturethe mixture heated
  9. temperatureunder reflux
  10. additionPetroleum ether (b.p. 100°-120° C.) (80 ml) was then added
  11. waitheld at 40° C. for 2 hours
  12. temperatureto cool to 30° C.
  13. stirringwas stirred overnight
  14. filtrationThe crystalline product was then filtered off
  15. washwashed with petroleum ether (b.p. 100°-120° C.)
  16. customdried at 65° C.

Sources & evidence

ORD record
ord-f26c0c524b5542a890f1c320b60baadd
Source dataset
uspto-grants-1993_12
Patent number
US05274118

Reaction notes

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