tert-Butanol → (1S,2S)-Ethyl 2-((S)-1-phenylethyl amino)cyclohexanecarboxylate

HRID 2065931Notes

Reaction equation

HRID 2065931 reaction equation
C(O)(C)(C)C.CC(C)([O-])C.[Na+].[C:12]1([C@@H:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[C:12]1([C@@H:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1

Participants

5

Reactant 3

HCID 6386tert-ButanolHCID 11065663(1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylateHCID 23676156Sodium t-butoxide

Product 1

HCID 11109723(1S,2S)-Ethyl 2-((S)-1-phenylethyl amino)cyclohexanecarboxylateYield 97.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
9 °C

Procedure

Tetrahydrofuran (1.25 L) was charged to a reactor followed by t-butanol (150 mL), and sodium t-butoxide (313 g) under nitrogen at ambient temperature. Additional tetrahydrofuran (1.0 L) was added and then the contents were cooled to <10° C. A solution of (1R,2S)-ethyl 2-((S)-1-phenylethylamino)cyclohexane carboxylate (9, 243.9 g) in tetrahydrofuran (300 mL) was added in NLT 30 minutes, while maintaining the temperature between 6-12° C. After the addition was complete, the mixture was warmed to 22° C. in NLT 30 minutes and further mixed for NLT 4 hours under nitrogen. The contents were cooled to <10° C. and the reaction was quenched with a solution of ammonium chloride (269.3 g) and water in NLT 30 minutes, while maintaining the temperature between 6-12° C. The lower aqueous layer was separated and extracted with 750 mL of heptanes. The upper organic layer was concentrated to about 0.8 L volume and extracted with the heptanes solution. The aqueous layer was separated and extracted with fresh heptanes (2×0.75 L) and the combined organic layers were washed with water (2×0.75 L) and 3.5 M aqueous sodium chloride solution (0.75 L), and dried with anhydrous magnesium sulfate. Concentration of the organic layer under vacuum gave 237.9 g of (1S,2S)-ethyl 2-((S)-1-phenylethyl amino)cyclohexane carboxylate (10) as a major isomer.

Workup

  1. temperaturethe contents were cooled to <10° C
  2. additionAfter the addition
  3. temperaturethe mixture was warmed to 22° C. in NLT 30 minutes
  4. additionfurther mixed for NLT 4 hours under nitrogen
  5. temperatureThe contents were cooled to <10° C.
  6. customthe reaction was quenched with a solution of ammonium chloride (269.3 g) and water in NLT 30 minutes
  7. temperaturewhile maintaining the temperature between 6-12° C
  8. customThe lower aqueous layer was separated
  9. extractionextracted with 750 mL of heptanes
  10. concentrationThe upper organic layer was concentrated to about 0.8 L volume
  11. extractionextracted with the heptanes solution
  12. customThe aqueous layer was separated
  13. extractionextracted with fresh heptanes (2×0.75 L)
  14. washthe combined organic layers were washed with water (2×0.75 L) and 3.5 M aqueous sodium chloride solution (0.75 L)
  15. dry with materialdried with anhydrous magnesium sulfate

Sources & evidence

ORD record
ord-435878c145b347ffa62441dd461d04d4
Source dataset
uspto-grants-2012_10
Patent number
US08288565B2

Reaction notes

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