Acetic Acid → (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate

HRID 2065930Notes

Reaction equation

HRID 2065930 reaction equation
C(O)(=O)C.[BH4-].[Na+].[C:7]1([C@@H:13]([NH:15][C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(#N)C>[C:7]1([C@@H:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 4311764Sodium borohydrideHCID 11737390(S)-Ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate

Product 1

HCID 11065663(1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylateYield 90%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
23 °C

Procedure

Acetic acid (1.0 L) was added to a reactor followed by sodium borohydride (100 g) with cooling between 16-30° C. under nitrogen in NLT 1 hour and mixed for NLT 30 minutes. Acetonitrile (500 mL) was added and mixed for NLT 30 minutes, and the cooled to below 5° C. A solution of (S)-ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate (8, 269 g) dissolved in acetonitrile (250 mL) was added in NLT 30 minutes, while maintaining the temperature between 2-8° C. and then the reaction mixture was warmed to 22° C., and mixed for NLT 4 hours. The mixture was cooled below 5° C. and quenched with 1.77 L of 25% aqueous sodium hydroxide solution, water (1.3 L) and heptanes (0.75 L) and the pH was adjusted pH to ˜8.0. The organic layer was separated and the aqueous layer was extracted with heptanes (2×0.75 L), and then the combined heptane layers were washed with water (2×0.75 L) and 3.5 M aqueous sodium chloride solution (0.75 L). The heptane solution was then dried using anhydrous magnesium sulfate and concentrated under vacuum to afford 243.9 g of (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate (9) as the major isomer.

Workup

  1. additionmixed for NLT 30 minutes
  2. additionmixed for NLT 30 minutes
  3. temperaturethe cooled to below 5° C
  4. additionwas added in NLT 30 minutes
  5. temperaturewhile maintaining the temperature between 2-8° C.
  6. temperaturethe reaction mixture was warmed to 22° C.
  7. additionmixed for NLT 4 hours
  8. temperatureThe mixture was cooled below 5° C.
  9. customquenched with 1.77 L of 25% aqueous sodium hydroxide solution, water (1.3 L) and heptanes (0.75 L)
  10. customThe organic layer was separated
  11. extractionthe aqueous layer was extracted with heptanes (2×0.75 L)
  12. washthe combined heptane layers were washed with water (2×0.75 L) and 3.5 M aqueous sodium chloride solution (0.75 L)
  13. dry with materialThe heptane solution was then dried
  14. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-445f38c3af5142a397f6d4d3cdf52837
Source dataset
uspto-grants-2012_10
Patent number
US08288565B2

Reaction notes

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